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EBI Dbfetch

ID   INSR_HUMAN              Reviewed;        1382 AA.
AC   P06213; Q17RW0; Q59H98; Q9UCB7; Q9UCB8; Q9UCB9;
DT   01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
DT   05-OCT-2010, sequence version 4.
DT   07-JAN-2015, entry version 209.
DE   RecName: Full=Insulin receptor;
DE            Short=IR;
DE            EC=2.7.10.1;
DE   AltName: CD_antigen=CD220;
DE   Contains:
DE     RecName: Full=Insulin receptor subunit alpha;
DE   Contains:
DE     RecName: Full=Insulin receptor subunit beta;
DE   Flags: Precursor;
GN   Name=INSR;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), AND VARIANTS GLY-2;
RP   HIS-171; THR-448 AND LYS-492.
RX   PubMed=2859121; DOI=10.1016/0092-8674(85)90334-4;
RA   Ebina Y., Ellis L., Jarnagin K., Edery M., Graf L., Clauser E.,
RA   Ou J.-H., Masiarz F., Kan Y.W., Goldfine I.D., Roth R.A., Rutter W.J.;
RT   "The human insulin receptor cDNA: the structural basis for hormone-
RT   activated transmembrane signalling.";
RL   Cell 40:747-758(1985).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT), PROTEIN SEQUENCE OF 28-49
RP   AND 763-782, GLYCOSYLATION AT ASN-43 AND ASN-769, AND VARIANT GLY-2.
RX   PubMed=2983222; DOI=10.1038/313756a0;
RA   Ullrich A., Bell J.R., Chen E.Y., Herrera R., Petruzzelli L.M.,
RA   Dull T.J., Gray A., Coussens L., Liao Y.-C., Tsubokawa M., Mason A.,
RA   Seeburg P.H., Grunfeld C., Rosen O.M., Ramachandran J.;
RT   "Human insulin receptor and its relationship to the tyrosine kinase
RT   family of oncogenes.";
RL   Nature 313:756-761(1985).
RN   [3]
RP   SEQUENCE REVISION TO 899-900.
RA   Chen E.Y.;
RL   Submitted (JUL-1985) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLY-2.
RC   TISSUE=Fetal liver;
RX   PubMed=2210055; DOI=10.2337/diacare.39.1.123;
RA   Seino S., Seino M., Bell G.I.;
RT   "Human insulin-receptor gene. Partial sequence and amplification of
RT   exons by polymerase chain reaction.";
RL   Diabetes 39:123-128(1990).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15057824; DOI=10.1038/nature02399;
RA   Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA   Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA   Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA   Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA   Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA   Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA   Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA   Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA   Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA   Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA   Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA   Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA   Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA   Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA   Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA   Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA   Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA   Rubin E.M., Lucas S.M.;
RT   "The DNA sequence and biology of human chromosome 19.";
RL   Nature 428:529-535(2004).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM SHORT), AND VARIANT
RP   GLY-2.
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA
RT   project: the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33, AND VARIANT GLY-2.
RX   PubMed=3680248;
RA   Araki E., Shimada F., Uzawa H., Mori M., Ebina Y.;
RT   "Characterization of the promoter region of the human insulin receptor
RT   gene. Evidence for promoter activity.";
RL   J. Biol. Chem. 262:16186-16191(1987).
RN   [8]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33, AND VARIANT GLY-2.
RX   PubMed=2806055; DOI=10.1016/0168-8227(89)90085-5;
RA   Araki E., Shimada F., Fukushima H., Mori M., Shichiri M., Ebina Y.;
RT   "Characterization of the promoter region of the human insulin receptor
RT   gene.";
RL   Diabetes Res. Clin. Pract. 7:S31-S33(1989).
RN   [9]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33, AND VARIANT GLY-2.
RX   PubMed=2777789;
RA   Tewari D.S., Cook D.M., Taub R.;
RT   "Characterization of the promoter region and 3' end of the human
RT   insulin receptor gene.";
RL   J. Biol. Chem. 264:16238-16245(1989).
RN   [10]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-33, AND VARIANT GLY-2.
RC   TISSUE=Skin fibroblast;
RX   PubMed=2280779; DOI=10.1210/mend-4-4-647;
RA   McKeon C., Moncada V., Pham T., Salvatore P., Kadowaki T., Accili D.,
RA   Taylor S.I.;
RT   "Structural and functional analysis of the insulin receptor
RT   promoter.";
RL   Mol. Endocrinol. 4:647-656(1990).
RN   [11]
RP   PROTEIN SEQUENCE OF 28-44; 192-205; 299-314; 610-627 AND 763-780,
RP   ENZYME REGULATION, AND SUBUNIT.
RC   TISSUE=Placenta;
RX   PubMed=2211730;
RA   Xu Q.-Y., Paxton R.J., Fujita-Yamaguchi Y.;
RT   "Substructural analysis of the insulin receptor by microsequence
RT   analyses of limited tryptic fragments isolated by sodium dodecyl
RT   sulfate-polyacrylamide gel electrophoresis in the absence or presence
RT   of dithiothreitol.";
RL   J. Biol. Chem. 265:18673-18681(1990).
RN   [12]
RP   PROTEIN SEQUENCE OF 28-45 AND 763-782, FUNCTION, AND FORMATION OF A
RP   HYBRID RECEPTOR WITH IGF1R.
RC   TISSUE=Placenta;
RX   PubMed=8257688; DOI=10.1021/bi00212a019;
RA   Kasuya J., Paz I.B., Maddux B.A., Goldfine I.D., Hefta S.A.,
RA   Fujita-Yamaguchi Y.;
RT   "Characterization of human placental insulin-like growth factor-
RT   I/insulin hybrid receptors by protein microsequencing and
RT   purification.";
RL   Biochemistry 32:13531-13536(1993).
RN   [13]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 538-1382 (ISOFORM SHORT).
RC   TISSUE=Brain;
RA   Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA   Ohara O., Nagase T., Kikuno R.F.;
RL   Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN   [14]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 728-772 (ISOFORM LONG), AND ALTERNATIVE
RP   SPLICING.
RX   PubMed=2538124; DOI=10.1016/0006-291X(89)92439-X;
RA   Seino S., Bell G.I.;
RT   "Alternative splicing of human insulin receptor messenger RNA.";
RL   Biochem. Biophys. Res. Commun. 159:312-316(1989).
RN   [15]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 744-823 (ISOFORM LONG), TISSUE
RP   SPECIFICITY, LIGAND-BINDING, AND AUTOPHOSPHORYLATION.
RX   PubMed=2369896;
RA   Mosthaf L., Grako K., Dull T.J., Coussens L., Ullrich A.,
RA   McClain D.A.;
RT   "Functionally distinct insulin receptors generated by tissue-specific
RT   alternative splicing.";
RL   EMBO J. 9:2409-2413(1990).
RN   [16]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 895-1085.
RX   PubMed=2566545; DOI=10.2337/diab.38.6.737;
RA   Elbein S.C.;
RT   "Molecular and clinical characterization of an insertional
RT   polymorphism of the insulin-receptor gene.";
RL   Diabetes 38:737-743(1989).
RN   [17]
RP   PROTEIN SEQUENCE OF 927-956; 981-1019; 1182-1194 AND 1352-1369, AND
RP   PHOSPHORYLATION AT TYR-999; TYR-1355 AND TYR-1361.
RC   TISSUE=Placenta;
RX   PubMed=3166375;
RA   Tavare J.M., Denton R.M.;
RT   "Studies on the autophosphorylation of the insulin receptor from human
RT   placenta. Analysis of the sites phosphorylated by two-dimensional
RT   peptide mapping.";
RL   Biochem. J. 252:607-615(1988).
RN   [18]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1006-1123.
RX   PubMed=2544997; DOI=10.1126/science.2544997;
RA   Taira M., Taira M., Hashimoto N., Shimada F., Suzuki Y., Kanatsuka A.,
RA   Nakamura F., Ebina Y., Tatibana M., Makino H.;
RT   "Human diabetes associated with a deletion of the tyrosine kinase
RT   domain of the insulin receptor.";
RL   Science 245:63-66(1989).
RN   [19]
RP   PARTIAL PROTEIN SEQUENCE.
RX   PubMed=3447155;
RA   Fujita-Yamaguchi Y., Hawke D., Shively J.E., Choi S.;
RT   "Partial amino acid sequence analyses of human placental insulin
RT   receptor.";
RL   Protein Seq. Data Anal. 1:3-6(1987).
RN   [20]
RP   MUTAGENESIS OF LYS-1057.
RX   PubMed=3101064; DOI=10.1073/pnas.84.3.704;
RA   Ebina Y., Araki E., Taira M., Shimada F., Mori M., Craik C.S.,
RA   Siddle K., Pierce S.B., Roth R.A., Rutter W.J.;
RT   "Replacement of lysine residue 1030 in the putative ATP-binding region
RT   of the insulin receptor abolishes insulin- and antibody-stimulated
RT   glucose uptake and receptor kinase activity.";
RL   Proc. Natl. Acad. Sci. U.S.A. 84:704-708(1987).
RN   [21]
RP   MUTAGENESIS OF TYR-999.
RX   PubMed=2842060; DOI=10.1016/S0092-8674(88)80008-4;
RA   White M.F., Livingston J.N., Backer J.M., Lauris V., Dull T.J.,
RA   Ullrich A., Kahn C.R.;
RT   "Mutation of the insulin receptor at tyrosine 960 inhibits signal
RT   transmission but does not affect its tyrosine kinase activity.";
RL   Cell 54:641-649(1988).
RN   [22]
RP   AUTOPHOSPHORYLATION.
RX   PubMed=1321605; DOI=10.1016/S0006-291X(05)80799-5;
RA   Dickens M., Tavare J.M.;
RT   "Analysis of the order of autophosphorylation of human insulin
RT   receptor tyrosines 1158, 1162 and 1163.";
RL   Biochem. Biophys. Res. Commun. 186:244-250(1992).
RN   [23]
RP   DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-541.
RX   PubMed=1472036; DOI=10.1016/0006-291X(92)92250-2;
RA   Schaeffer L., Ljungqvist L.;
RT   "Identification of a disulfide bridge connecting the alpha-subunits of
RT   the extracellular domain of the insulin receptor.";
RL   Biochem. Biophys. Res. Commun. 189:650-653(1992).
RN   [24]
RP   FUNCTION, AND FORMATION OF A HYBRID RECEPTOR WITH IGF1R.
RX   PubMed=8452530;
RA   Soos M.A., Field C.E., Siddle K.;
RT   "Purified hybrid insulin/insulin-like growth factor-I receptors bind
RT   insulin-like growth factor-I, but not insulin, with high affinity.";
RL   Biochem. J. 290:419-426(1993).
RN   [25]
RP   FUNCTION, AND INTERACTION WITH PIK3R1.
RX   PubMed=8276809;
RA   Van Horn D.J., Myers M.G. Jr., Backer J.M.;
RT   "Direct activation of the phosphatidylinositol 3'-kinase by the
RT   insulin receptor.";
RL   J. Biol. Chem. 269:29-32(1994).
RN   [26]
RP   INTERACTION WITH IRS1 AND SHC1, AND MUTAGENESIS OF LEU-991; TYR-992;
RP   ASN-996; 996-ASN-PRO-997; PRO-997; TYR-999; LEU-1000 AND ALA-1002.
RX   PubMed=7559478; DOI=10.1074/jbc.270.40.23258;
RA   He W., O'Neill T.J., Gustafson T.A.;
RT   "Distinct modes of interaction of SHC and insulin receptor substrate-1
RT   with the insulin receptor NPEY region via non-SH2 domains.";
RL   J. Biol. Chem. 270:23258-23262(1995).
RN   [27]
RP   INTERACTION WITH IRS1; SHC1 AND PIK3R1, AND MUTAGENESIS OF ASN-996;
RP   PRO-997; GLU-998; TYR-999 AND LYS-1057.
RX   PubMed=7537849;
RA   Gustafson T.A., He W., Craparo A., Schaub C.D., O'Neill T.J.;
RT   "Phosphotyrosine-dependent interaction of SHC and insulin receptor
RT   substrate 1 with the NPEY motif of the insulin receptor via a novel
RT   non-SH2 domain.";
RL   Mol. Cell. Biol. 15:2500-2508(1995).
RN   [28]
RP   FORMATION OF A HYBRID RECEPTOR WITH IGF1R, AND TISSUE SPECIFICITY.
RX   PubMed=9355755;
RA   Bailyes E.M., Nave B.T., Soos M.A., Orr S.R., Hayward A.C., Siddle K.;
RT   "Insulin receptor/IGF-I receptor hybrids are widely distributed in
RT   mammalian tissues: quantification of individual receptor species by
RT   selective immunoprecipitation and immunoblotting.";
RL   Biochem. J. 327:209-215(1997).
RN   [29]
RP   FUNCTION IN PHOSPHORYLATION OF STAT5B, MUTAGENESIS OF TYR-999, AND
RP   INTERACTION WITH STAT5B; IRS1 AND IRS2.
RX   PubMed=9428692; DOI=10.1111/j.1432-1033.1997.0411a.x;
RA   Sawka-Verhelle D., Filloux C., Tartare-Deckert S., Mothe I.,
RA   Van Obberghen E.;
RT   "Identification of Stat 5B as a substrate of the insulin receptor.";
RL   Eur. J. Biochem. 250:411-417(1997).
RN   [30]
RP   INTERACTION WITH PTPRF.
RX   PubMed=8995282; DOI=10.1074/jbc.272.11.7519;
RA   Ahmad F., Goldstein B.J.;
RT   "Functional association between the insulin receptor and the
RT   transmembrane protein-tyrosine phosphatase LAR in intact cells.";
RL   J. Biol. Chem. 272:448-457(1997).
RN   [31]
RP   INTERACTION WITH PTPRE, AND DEPHOSPHORYLATION BY PTPRE.
RX   PubMed=8999839; DOI=10.1074/jbc.272.3.1639;
RA   Bandyopadhyay D., Kusari A., Kenner K.A., Liu F., Chernoff J.,
RA   Gustafson T.A., Kusari J.;
RT   "Protein-tyrosine phosphatase 1B complexes with the insulin receptor
RT   in vivo and is tyrosine-phosphorylated in the presence of insulin.";
RL   J. Biol. Chem. 272:1639-1645(1997).
RN   [32]
RP   FORMATION OF A HYBRID RECEPTOR WITH IGF1R, AND TISSUE SPECIFICITY.
RX   PubMed=9202395; DOI=10.1016/S0303-7207(97)04050-1;
RA   Federici M., Porzio O., Zucaro L., Fusco A., Borboni P., Lauro D.,
RA   Sesti G.;
RT   "Distribution of insulin/insulin-like growth factor-I hybrid receptors
RT   in human tissues.";
RL   Mol. Cell. Endocrinol. 129:121-126(1997).
RN   [33]
RP   TISSUE SPECIFICITY, AND FUNCTION AS RECEPTOR FOR IGFII (ISOFORM
RP   SHORT).
RX   PubMed=10207053;
RA   Frasca F., Pandini G., Scalia P., Sciacca L., Mineo R., Costantino A.,
RA   Goldfine I.D., Belfiore A., Vigneri R.;
RT   "Insulin receptor isoform A, a newly recognized, high-affinity
RT   insulin-like growth factor II receptor in fetal and cancer cells.";
RL   Mol. Cell. Biol. 19:3278-3288(1999).
RN   [34]
RP   INTERACTION WITH ENPP1, AND ENZYME REGULATION.
RX   PubMed=10615944; DOI=10.2337/diabetes.49.1.13;
RA   Maddux B.A., Goldfine I.D.;
RT   "Membrane glycoprotein PC-1 inhibition of insulin receptor function
RT   occurs via direct interaction with the receptor alpha-subunit.";
RL   Diabetes 49:13-19(2000).
RN   [35]
RP   PHOSPHORYLATION, AND DEPHOSPHORYLATION BY PTPN1 AND PTPN2.
RX   PubMed=10734133; DOI=10.1074/jbc.275.13.9792;
RA   Waelchli S., Curchod M.L., Gobert R.P., Arkinstall S.,
RA   Hooft van Huijsduijnen R.;
RT   "Identification of tyrosine phosphatases that dephosphorylate the
RT   insulin receptor. A brute force approach based on 'substrate-trapping'
RT   mutants.";
RL   J. Biol. Chem. 275:9792-9796(2000).
RN   [36]
RP   INTERACTION WITH GRB7, AND MUTAGENESIS OF LYS-1057; TYR-1189 AND
RP   TYR-1190.
RX   PubMed=10803466; DOI=10.1038/sj.onc.1203469;
RA   Kasus-Jacobi A., Bereziat V., Perdereau D., Girard J., Burnol A.F.;
RT   "Evidence for an interaction between the insulin receptor and Grb7. A
RT   role for two of its binding domains, PIR and SH2.";
RL   Oncogene 19:2052-2059(2000).
RN   [37]
RP   INTERACTION WITH SORBS1.
RX   PubMed=11374898; DOI=10.1006/geno.2001.6541;
RA   Lin W.-H., Huang C.-J., Liu M.-W., Chang H.-M., Chen Y.-J., Tai T.-Y.,
RA   Chuang L.-M.;
RT   "Cloning, mapping, and characterization of the human sorbin and SH3
RT   domain containing 1 (SORBS1) gene: a protein associated with c-Abl
RT   during insulin signaling in the hepatoma cell line Hep3B.";
RL   Genomics 74:12-20(2001).
RN   [38]
RP   CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-1159 AND ARG-1163, AND ENZYME
RP   REGULATION.
RX   PubMed=11598120; DOI=10.1074/jbc.M107236200;
RA   Ablooglu A.J., Frankel M., Rusinova E., Ross J.B., Kohanski R.A.;
RT   "Multiple activation loop conformations and their regulatory
RT   properties in the insulin receptor's kinase domain.";
RL   J. Biol. Chem. 276:46933-46940(2001).
RN   [39]
RP   INTERACTION WITH GRB14, AND ENZYME REGULATION.
RX   PubMed=11726652; DOI=10.1074/jbc.M106574200;
RA   Bereziat V., Kasus-Jacobi A., Perdereau D., Cariou B., Girard J.,
RA   Burnol A.F.;
RT   "Inhibition of insulin receptor catalytic activity by the molecular
RT   adapter Grb14.";
RL   J. Biol. Chem. 277:4845-4852(2002).
RN   [40]
RP   FUNCTION, AND FORMATION OF A HYBRID RECEPTOR WITH IGF1R.
RX   PubMed=12138094; DOI=10.1074/jbc.M202766200;
RA   Pandini G., Frasca F., Mineo R., Sciacca L., Vigneri R., Belfiore A.;
RT   "Insulin/insulin-like growth factor I hybrid receptors have different
RT   biological characteristics depending on the insulin receptor isoform
RT   involved.";
RL   J. Biol. Chem. 277:39684-39695(2002).
RN   [41]
RP   INTERACTION WITH GRB10, AND ENZYME REGULATION.
RX   PubMed=12493740; DOI=10.1074/jbc.M208518200;
RA   Wick K.R., Werner E.D., Langlais P., Ramos F.J., Dong L.Q.,
RA   Shoelson S.E., Liu F.;
RT   "Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-
RT   phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the
RT   association of IRS-1/IRS-2 with the insulin receptor.";
RL   J. Biol. Chem. 278:8460-8467(2003).
RN   [42]
RP   PHOSPHORYLATION, AND DEPHOSPHORYLATION BY PTPN2.
RX   PubMed=12612081; DOI=10.1128/MCB.23.6.2096-2108.2003;
RA   Galic S., Klingler-Hoffmann M., Fodero-Tavoletti M.T., Puryer M.A.,
RA   Meng T.C., Tonks N.K., Tiganis T.;
RT   "Regulation of insulin receptor signaling by the protein tyrosine
RT   phosphatase TCPTP.";
RL   Mol. Cell. Biol. 23:2096-2108(2003).
RN   [43]
RP   INTERACTION WITH SOCS7.
RX   PubMed=16127460; DOI=10.1172/JCI23853;
RA   Banks A.S., Li J., McKeag L., Hribal M.L., Kashiwada M., Accili D.,
RA   Rothman P.B.;
RT   "Deletion of SOCS7 leads to enhanced insulin action and enlarged
RT   islets of Langerhans.";
RL   J. Clin. Invest. 115:2462-2471(2005).
RN   [44]
RP   FUNCTION IN PHOSPHORYLATION OF PDPK1, AND INTERACTION WITH PDPK1.
RX   PubMed=16314505; DOI=10.1128/MCB.25.24.10803-10814.2005;
RA   Fiory F., Alberobello A.T., Miele C., Oriente F., Esposito I.,
RA   Corbo V., Ruvo M., Tizzano B., Rasmussen T.E., Gammeltoft S.,
RA   Formisano P., Beguinot F.;
RT   "Tyrosine phosphorylation of phosphoinositide-dependent kinase 1 by
RT   the insulin receptor is necessary for insulin metabolic signaling.";
RL   Mol. Cell. Biol. 25:10803-10814(2005).
RN   [45]
RP   DEPHOSPHORYLATION BY PTPRE.
RX   PubMed=15738637; DOI=10.2108/zsj.22.169;
RA   Nakagawa Y., Aoki N., Aoyama K., Shimizu H., Shimano H., Yamada N.,
RA   Miyazaki H.;
RT   "Receptor-type protein tyrosine phosphatase epsilon (PTPepsilonM) is a
RT   negative regulator of insulin signaling in primary hepatocytes and
RT   liver.";
RL   Zool. Sci. 22:169-175(2005).
RN   [46]
RP   FUNCTION, AND FORMATION OF A HYBRID RECEPTOR WITH IGF1R.
RX   PubMed=16831875; DOI=10.1074/jbc.M605189200;
RA   Slaaby R., Schaeffer L., Lautrup-Larsen I., Andersen A.S., Shaw A.C.,
RA   Mathiasen I.S., Brandt J.;
RT   "Hybrid receptors formed by insulin receptor (IR) and insulin-like
RT   growth factor I receptor (IGF-IR) have low insulin and high IGF-1
RT   affinity irrespective of the IR splice variant.";
RL   J. Biol. Chem. 281:25869-25874(2006).
RN   [47]
RP   REVIEW ON SIGNALING PATHWAYS.
RX   PubMed=16493415; DOI=10.1038/nrg1767;
RA   Taniguchi C.M., Emanuelli B., Kahn C.R.;
RT   "Critical nodes in signalling pathways: insights into insulin
RT   action.";
RL   Nat. Rev. Mol. Cell Biol. 7:85-96(2006).
RN   [48]
RP   REVIEW ON REGULATION OF INSR FUNCTION.
RX   PubMed=17347799; DOI=10.1007/s00018-007-6359-9;
RA   Youngren J.F.;
RT   "Regulation of insulin receptor function.";
RL   Cell. Mol. Life Sci. 64:873-891(2007).
RN   [49]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-400; TYR-401 AND
RP   SER-407, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP   ANALYSIS].
RC   TISSUE=Cervix carcinoma;
RX   PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA   Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA   Elledge S.J., Gygi S.P.;
RT   "A quantitative atlas of mitotic phosphorylation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN   [50]
RP   DOMAIN, AND INSULIN-BINDING SITE.
RX   PubMed=19459609; DOI=10.1021/bi900261q;
RA   Menting J.G., Ward C.W., Margetts M.B., Lawrence M.C.;
RT   "A thermodynamic study of ligand binding to the first three domains of
RT   the human insulin receptor: relationship between the receptor alpha-
RT   chain C-terminal peptide and the site 1 insulin mimetic peptides.";
RL   Biochemistry 48:5492-5500(2009).
RN   [51]
RP   GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-242 AND ASN-541.
RC   TISSUE=Liver;
RX   PubMed=19159218; DOI=10.1021/pr8008012;
RA   Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT   "Glycoproteomics analysis of human liver tissue by combination of
RT   multiple enzyme digestion and hydrazide chemistry.";
RL   J. Proteome Res. 8:651-661(2009).
RN   [52]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA   Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA   Mann M., Daub H.;
RT   "Large-scale proteomics analysis of the human kinome.";
RL   Mol. Cell. Proteomics 8:1751-1764(2009).
RN   [53]
RP   GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-445 AND ASN-920.
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19349973; DOI=10.1038/nbt.1532;
RA   Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA   Schiess R., Aebersold R., Watts J.D.;
RT   "Mass-spectrometric identification and relative quantification of N-
RT   linked cell surface glycoproteins.";
RL   Nat. Biotechnol. 27:378-386(2009).
RN   [54]
RP   X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1005-1310.
RX   PubMed=7997262; DOI=10.1038/372746a0;
RA   Hubbard S.R., Wei L., Ellis L., Hendrickson W.A.;
RT   "Crystal structure of the tyrosine kinase domain of the human insulin
RT   receptor.";
RL   Nature 372:746-754(1994).
RN   [55]
RP   X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH
RP   ATP ANALOG AND IRS1 PEPTIDE, CATALYTIC ACTIVITY, ACTIVE SITE,
RP   AUTOPHOSPHORYLATION, AND PHOSPHORYLATION AT TYR-1185; TYR-1189 AND
RP   TYR-1190.
RX   PubMed=9312016; DOI=10.1093/emboj/16.18.5572;
RA   Hubbard S.R.;
RT   "Crystal structure of the activated insulin receptor tyrosine kinase
RT   in complex with peptide substrate and ATP analog.";
RL   EMBO J. 16:5572-5581(1997).
RN   [56]
RP   X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH
RP   ATP ANALOG, AND CATALYTIC ACTIVITY.
RX   PubMed=11124964; DOI=10.1074/jbc.M010161200;
RA   Till J.H., Ablooglu A.J., Frankel M., Bishop S.M., Kohanski R.A.,
RA   Hubbard S.R.;
RT   "Crystallographic and solution studies of an activation loop mutant of
RT   the insulin receptor tyrosine kinase: insights into kinase
RT   mechanism.";
RL   J. Biol. Chem. 276:10049-10055(2001).
RN   [57]
RP   X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 1005-1298 OF MUTANT
RP   ASN-1159, CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF
RP   TYR-1011.
RX   PubMed=12707268; DOI=10.1074/jbc.M302425200;
RA   Li S., Covino N.D., Stein E.G., Till J.H., Hubbard S.R.;
RT   "Structural and biochemical evidence for an autoinhibitory role for
RT   tyrosine 984 in the juxtamembrane region of the insulin receptor.";
RL   J. Biol. Chem. 278:26007-26014(2003).
RN   [58]
RP   X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH ATP
RP   ANALOG AND SH2B2, AND PHOSPHORYLATION AT TYR-1185; TYR-1189 AND
RP   TYR-1190.
RX   PubMed=14690593; DOI=10.1016/S1097-2765(03)00487-8;
RA   Hu J., Liu J., Ghirlando R., Saltiel A.R., Hubbard S.R.;
RT   "Structural basis for recruitment of the adaptor protein APS to the
RT   activated insulin receptor.";
RL   Mol. Cell 12:1379-1389(2003).
RN   [59]
RP   X-RAY CRYSTALLOGRAPHY (3.20 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH
RP   GRB14, INTERACTION WITH GRB14, AUTOPHOSPHORYLATION, AND
RP   PHOSPHORYLATION AT TYR-1185; TYR-1189 AND TYR-1190.
RX   PubMed=16246733; DOI=10.1016/j.molcel.2005.09.001;
RA   Depetris R.S., Hu J., Gimpelevich I., Holt L.J., Daly R.J.,
RA   Hubbard S.R.;
RT   "Structural basis for inhibition of the insulin receptor by the
RT   adaptor protein Grb14.";
RL   Mol. Cell 20:325-333(2005).
RN   [60]
RP   X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH
RP   PTPN1, AND PHOSPHORYLATION AT TYR-1185; TYR-1189 AND TYR-1190.
RX   PubMed=16271887; DOI=10.1016/j.str.2005.07.019;
RA   Li S., Depetris R.S., Barford D., Chernoff J., Hubbard S.R.;
RT   "Crystal structure of a complex between protein tyrosine phosphatase
RT   1B and the insulin receptor tyrosine kinase.";
RL   Structure 13:1643-1651(2005).
RN   [61]
RP   X-RAY CRYSTALLOGRAPHY (3.8 ANGSTROMS) OF 28-943 IN COMPLEX WITH
RP   INSULIN ANALOG, DOMAIN, AND DISULFIDE BONDS.
RX   PubMed=16957736; DOI=10.1038/nature05106;
RA   McKern N.M., Lawrence M.C., Streltsov V.A., Lou M.Z., Adams T.E.,
RA   Lovrecz G.O., Elleman T.C., Richards K.M., Bentley J.D., Pilling P.A.,
RA   Hoyne P.A., Cartledge K.A., Pham T.M., Lewis J.L., Sankovich S.E.,
RA   Stoichevska V., Da Silva E., Robinson C.P., Frenkel M.J.,
RA   Sparrow L.G., Fernley R.T., Epa V.C., Ward C.W.;
RT   "Structure of the insulin receptor ectodomain reveals a folded-over
RT   conformation.";
RL   Nature 443:218-221(2006).
RN   [62]
RP   X-RAY CRYSTALLOGRAPHY (2.32 ANGSTROMS) OF 28-512, GLYCOSYLATION AT
RP   ASN-43; ASN-52; ASN-138; ASN-242; ASN-282; ASN-364; ASN-424 AND
RP   ASN-445, AND DISULFIDE BONDS.
RX   PubMed=16894147; DOI=10.1073/pnas.0605395103;
RA   Lou M., Garrett T.P., McKern N.M., Hoyne P.A., Epa V.C., Bentley J.D.,
RA   Lovrecz G.O., Cosgrove L.J., Frenkel M.J., Ward C.W.;
RT   "The first three domains of the insulin receptor differ structurally
RT   from the insulin-like growth factor 1 receptor in the regions
RT   governing ligand specificity.";
RL   Proc. Natl. Acad. Sci. U.S.A. 103:12429-12434(2006).
RN   [63]
RP   X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH
RP   ATP AND IRS2, CATALYTIC ACTIVITY, PHOSPHORYLATION AT TYR-1185;
RP   TYR-1189 AND TYR-1190, AND INTERACTION WITH IRS2.
RX   PubMed=18278056; DOI=10.1038/nsmb.1388;
RA   Wu J., Tseng Y.D., Xu C.F., Neubert T.A., White M.F., Hubbard S.R.;
RT   "Structural and biochemical characterization of the KRLB region in
RT   insulin receptor substrate-2.";
RL   Nat. Struct. Mol. Biol. 15:251-258(2008).
RN   [64]
RP   X-RAY CRYSTALLOGRAPHY (3.25 ANGSTROMS) OF 1009-1310 IN COMPLEX WITH
RP   INHIBITORY PEPTIDE, AND PHOSPHORYLATION AT TYR-1185; TYR-1189 AND
RP   TYR-1190.
RX   PubMed=18767165; DOI=10.1002/prot.22207;
RA   Katayama N., Orita M., Yamaguchi T., Hisamichi H., Kuromitsu S.,
RA   Kurihara H., Sakashita H., Matsumoto Y., Fujita S., Niimi T.;
RT   "Identification of a key element for hydrogen-bonding patterns between
RT   protein kinases and their inhibitors.";
RL   Proteins 73:795-801(2008).
RN   [65]
RP   X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH
RP   SYNTHETIC INHIBITOR, AND CATALYTIC ACTIVITY.
RX   PubMed=19071018; DOI=10.1016/j.bmcl.2008.11.077;
RA   Chamberlain S.D., Redman A.M., Wilson J.W., Deanda F., Shotwell J.B.,
RA   Gerding R., Lei H., Yang B., Stevens K.L., Hassell A.M.,
RA   Shewchuk L.M., Leesnitzer M.A., Smith J.L., Sabbatini P., Atkins C.,
RA   Groy A., Rowand J.L., Kumar R., Mook R.A. Jr., Moorthy G., Patnaik S.;
RT   "Optimization of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine IGF-1R
RT   tyrosine kinase inhibitors towards JNK selectivity.";
RL   Bioorg. Med. Chem. Lett. 19:360-364(2009).
RN   [66]
RP   X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1005-1310 IN COMPLEX WITH
RP   SYNTHETIC INHIBITOR, AND CATALYTIC ACTIVITY.
RX   PubMed=19056263; DOI=10.1016/j.bmcl.2008.11.046;
RA   Chamberlain S.D., Wilson J.W., Deanda F., Patnaik S., Redman A.M.,
RA   Yang B., Shewchuk L., Sabbatini P., Leesnitzer M.A., Groy A.,
RA   Atkins C., Gerding R., Hassell A.M., Lei H., Mook R.A. Jr.,
RA   Moorthy G., Rowand J.L., Stevens K.L., Kumar R., Shotwell J.B.;
RT   "Discovery of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines: potent
RT   inhibitors of the IGF-1R receptor tyrosine kinase.";
RL   Bioorg. Med. Chem. Lett. 19:469-473(2009).
RN   [67]
RP   X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 1017-1322 IN COMPLEX WITH
RP   SYNTHETIC INHIBITOR, AND CATALYTIC ACTIVITY.
RX   PubMed=19394223; DOI=10.1016/j.bmcl.2008.12.110;
RA   Patnaik S., Stevens K.L., Gerding R., Deanda F., Shotwell J.B.,
RA   Tang J., Hamajima T., Nakamura H., Leesnitzer M.A., Hassell A.M.,
RA   Shewchuck L.M., Kumar R., Lei H., Chamberlain S.D.;
RT   "Discovery of 3,5-disubstituted-1H-pyrrolo[2,3-b]pyridines as potent
RT   inhibitors of the insulin-like growth factor-1 receptor (IGF-1R)
RT   tyrosine kinase.";
RL   Bioorg. Med. Chem. Lett. 19:3136-3140(2009).
RN   [68]
RP   X-RAY CRYSTALLOGRAPHY (3.80 ANGSTROMS) OF 28-956, INSULIN-BINDING
RP   REGION, AND DISULFIDE BONDS.
RX   PubMed=20348418; DOI=10.1073/pnas.1001813107;
RA   Smith B.J., Huang K., Kong G., Chan S.J., Nakagawa S., Menting J.G.,
RA   Hu S.Q., Whittaker J., Steiner D.F., Katsoyannis P.G., Ward C.W.,
RA   Weiss M.A., Lawrence M.C.;
RT   "Structural resolution of a tandem hormone-binding element in the
RT   insulin receptor and its implications for design of peptide
RT   agonists.";
RL   Proc. Natl. Acad. Sci. U.S.A. 107:6771-6776(2010).
RN   [69]
RP   X-RAY CRYSTALLOGRAPHY (3.9 ANGSTROMS) OF 28-620 IN COMPLEX WITH
RP   INSULIN, DOMAIN, GLYCOSYLATION AT ASN-43; ASN-52; ASN-138; ASN-242 AND
RP   ASN-282, AND DISULFIDE BONDS.
RX   PubMed=23302862; DOI=10.1038/nature11781;
RA   Menting J.G., Whittaker J., Margetts M.B., Whittaker L.J., Kong G.K.,
RA   Smith B.J., Watson C.J., Zakova L., Kletvikova E., Jiracek J.,
RA   Chan S.J., Steiner D.F., Dodson G.G., Brzozowski A.M., Weiss M.A.,
RA   Ward C.W., Lawrence M.C.;
RT   "How insulin engages its primary binding site on the insulin
RT   receptor.";
RL   Nature 493:241-245(2013).
RN   [70]
RP   VARIANT IRAN TYPE A SER-762.
RX   PubMed=3283938; DOI=10.1126/science.3283938;
RA   Yoshimasa Y., Seino S., Whittaker J., Kakehi T., Kosaki A., Kuzuya H.,
RA   Imura H., Bell G.I., Steiner D.F.;
RT   "Insulin-resistant diabetes due to a point mutation that prevents
RT   insulin proreceptor processing.";
RL   Science 240:784-787(1988).
RN   [71]
RP   VARIANT LEPRCH GLU-487.
RX   PubMed=2834824; DOI=10.1126/science.2834824;
RA   Kadowaki T., Bevins C., Cama A., Ojamaa K., Marcus-Samuels B.,
RA   Kadowaki H., Beitz L., McKeon C., Taylor S.I.;
RT   "Two mutant alleles of the insulin receptor gene in a patient with
RT   extreme insulin resistance.";
RL   Science 240:787-790(1988).
RN   [72]
RP   VARIANT LEPRCH PRO-260.
RX   PubMed=2479553;
RA   Klinkhamer M.P., Groen N.A., van der Zon G.C.M., Lindhout D.,
RA   Sandkuyl L.A., Krans H.M.J., Moeller W., Maassen J.A.;
RT   "A leucine-to-proline mutation in the insulin receptor in a family
RT   with insulin resistance.";
RL   EMBO J. 8:2503-2507(1989).
RN   [73]
RP   VARIANT IRAN TYPE A VAL-1035.
RX   PubMed=2544998; DOI=10.1126/science.2544998;
RA   Odawara M., Kadowaki T., Yamamoto R., Shibasaki Y., Tobe K.,
RA   Accili D., Bevins C., Mikami Y., Matsuura N., Akanuma Y., Takaku F.,
RA   Taylor S.I., Kasuga M.;
RT   "Human diabetes associated with a mutation in the tyrosine kinase
RT   domain of the insulin receptor.";
RL   Science 245:66-68(1989).
RN   [74]
RP   VARIANT IRAN TYPE A THR-1161.
RX   PubMed=2168397;
RA   Moller D.E., Yokota A., White M.F., Pazianos A.G., Flier J.S.;
RT   "A naturally occurring mutation of insulin receptor alanine 1134
RT   impairs tyrosine kinase function and is associated with dominantly
RT   inherited insulin resistance.";
RL   J. Biol. Chem. 265:14979-14985(1990).
RN   [75]
RP   CHARACTERIZATION OF VARIANT RMS LYS-42.
RX   PubMed=2121734;
RA   Kadowaki T., Kadowaki H., Accili D., Taylor S.I.;
RT   "Substitution of lysine for asparagine at position 15 in the alpha-
RT   subunit of the human insulin receptor. A mutation that impairs
RT   transport of receptors to the cell surface and decreases the affinity
RT   of insulin binding.";
RL   J. Biol. Chem. 265:19143-19150(1990).
RN   [76]
RP   VARIANT RMS LYS-42, VARIANT LEPRCH ARG-236, AND VARIANT IRAN TYPE A
RP   SER-489.
RX   PubMed=2365819; DOI=10.1172/JCI114693;
RA   Kadowaki T., Kadowaki H., Rechler M.M., Serrano-Rios M., Roth J.,
RA   Gorden P., Taylor S.I.;
RT   "Five mutant alleles of the insulin receptor gene in patients with
RT   genetic forms of insulin resistance.";
RL   J. Clin. Invest. 86:254-264(1990).
RN   [77]
RP   VARIANT IRAN TYPE A SER-1227.
RX   PubMed=1963473; DOI=10.1210/mend-4-8-1183;
RA   Moller D.E., Yokota A., Ginsberg-Fellner F., Flier J.S.;
RT   "Functional properties of a naturally occurring Trp1200-->Ser1200
RT   mutation of the insulin receptor.";
RL   Mol. Endocrinol. 4:1183-1191(1990).
RN   [78]
RP   VARIANT GLU-1095.
RX   PubMed=2040394; DOI=10.2337/diab.40.6.777;
RA   O'Rahilly S., Choi W.H., Patel P., Turner R.C., Flier J.S.,
RA   Moller D.E.;
RT   "Detection of mutations in insulin-receptor gene in NIDDM patients by
RT   analysis of single-stranded conformation polymorphisms.";
RL   Diabetes 40:777-782(1991).
RN   [79]
RP   VARIANT IRAN TYPE A GLN-1020.
RX   PubMed=2002058;
RA   Kusari J., Takata Y., Hatada E., Freidenberg G., Kolterman O.,
RA   Olefsky J.M.;
RT   "Insulin resistance and diabetes due to different mutations in the
RT   tyrosine kinase domain of both insulin receptor gene alleles.";
RL   J. Biol. Chem. 266:5260-5267(1991).
RN   [80]
RP   VARIANT INS RESISTANCE ILE-1180.
RX   PubMed=1890161; DOI=10.1210/jcem-73-4-894;
RA   Cama A., de la Luz Sierra M., Ottini L., Kadowaki T., Gorden P.,
RA   Imperato-Mcginley J., Taylor S.I.;
RT   "A mutation in the tyrosine kinase domain of the insulin receptor
RT   associated with insulin resistance in an obese woman.";
RL   J. Clin. Endocrinol. Metab. 73:894-901(1991).
RN   [81]
RP   VARIANTS LEPRCH ALA-55 AND ARG-393.
RX   PubMed=1607067; DOI=10.2337/diab.41.4.408;
RA   Barbetti F., Gejman P.V., Taylor S.I., Raben N., Cama A., Bonora E.,
RA   Pizzo P., Moghetti P., Muggeo M., Roth J.;
RT   "Detection of mutations in insulin receptor gene by denaturing
RT   gradient gel electrophoresis.";
RL   Diabetes 41:408-415(1992).
RN   [82]
RP   VARIANT NIDDM GLN-1191.
RX   PubMed=1607076; DOI=10.2337/diab.41.4.521;
RA   Cocozza S., Porcellini A., Riccardi G., Monticelli A., Condorelli G.,
RA   Ferrara A., Pianese L., Miele C., Capaldo B., Beguinot F., Varrone S.;
RT   "NIDDM associated with mutation in tyrosine kinase domain of insulin
RT   receptor gene.";
RL   Diabetes 41:521-526(1992).
RN   [83]
RP   VARIANT IRAN TYPE A LEU-1205.
RX   PubMed=1563582; DOI=10.1007/BF00400927;
RA   Kim H., Kadowaki H., Sakura H., Odawara M., Momomura K., Takahashi Y.,
RA   Miyazaki Y., Ohtani T., Akanuma Y., Yazaki Y., Kasuga M., Taylor S.I.,
RA   Kadowaki T.;
RT   "Detection of mutations in the insulin receptor gene in patients with
RT   insulin resistance by analysis of single-stranded conformational
RT   polymorphisms.";
RL   Diabetologia 35:261-266(1992).
RN   [84]
RP   VARIANT LEPRCH ARG-58.
RX   PubMed=1730625;
RA   van der Vorm E.R., van der Zon G.C.M., Moeller W., Krans H.M.J.,
RA   Lindhout D., Maassen J.A.;
RT   "An Arg for Gly substitution at position 31 in the insulin receptor,
RT   linked to insulin resistance, inhibits receptor processing and
RT   transport.";
RL   J. Biol. Chem. 267:66-71(1992).
RN   [85]
RP   VARIANT NIDDM GLN-1158.
RX   PubMed=1470163;
RA   Kasuga M., Kishimoto M., Hashiramoto M., Yonezawa K., Kazumi T.,
RA   Hagino H., Shii K.;
RT   "Insulin receptor Arg1131-->Gln: a novel mutation in the catalytic
RT   loop of insulin receptor observed in insulin resistant diabetes.";
RL   Nihon Geka Gakkai Zasshi 93:968-971(1992).
RN   [86]
RP   VARIANT MET-1012.
RX   PubMed=8432414; DOI=10.2337/diab.42.3.429;
RA   Elbein S.C., Sorensen L.K., Schumacher M.C.;
RT   "Methionine for valine substitution in exon 17 of the insulin receptor
RT   gene in a pedigree with familial NIDDM.";
RL   Diabetes 42:429-434(1993).
RN   [87]
RP   VARIANT IRAN TYPE A ASP-1075.
RX   PubMed=8243830; DOI=10.2337/diab.42.12.1837;
RA   Haruta T., Takata Y., Iwanishi M., Maegawa H., Imamura T., Egawa K.,
RA   Itazu T., Kobayashi M.;
RT   "Ala1048-->Asp mutation in the kinase domain of insulin receptor
RT   causes defective kinase activity and insulin resistance.";
RL   Diabetes 42:1837-1844(1993).
RN   [88]
RP   VARIANT MET-1012.
RX   PubMed=8458533; DOI=10.1007/BF00400701;
RA   van der Vorm E.R., Kuipers A., Bonenkamp J.W., Kleijer W.J.,
RA   van Maldergem L., Herwig J., Maassen J.A.;
RT   "Patients with lipodystrophic diabetes mellitus of the Seip-
RT   Berardinelli type, express normal insulin receptors.";
RL   Diabetologia 36:172-174(1993).
RN   [89]
RP   VARIANT INS RESISTANCE LEU-1220.
RX   PubMed=8390949; DOI=10.1007/BF00402277;
RA   Iwanishi M., Haruta T., Takata Y., Ishibashi O., Sasaoka T., Egawa K.,
RA   Imamura T., Naitou K., Itazu T., Kobayashi M.;
RT   "A mutation (Trp1193-->Leu1193) in the tyrosine kinase domain of the
RT   insulin receptor associated with type A syndrome of insulin
RT   resistance.";
RL   Diabetologia 36:414-422(1993).
RN   [90]
RP   VARIANT INS RESISTANCE LEU-220.
RX   PubMed=8242067; DOI=10.1093/hmg/2.9.1437;
RA   Carrera P., Cordera R., Ferrari M., Cremonesi L., Taramelli R.,
RA   Andraghetti G., Carducci C., Dozio N., Pozza G., Taylor S.I.,
RA   Micossi P., Barbetti F.;
RT   "Substitution of Leu for Pro-193 in the insulin receptor in a patient
RT   with a genetic form of severe insulin resistance.";
RL   Hum. Mol. Genet. 2:1437-1441(1993).
RN   [91]
RP   CHARACTERIZATION OF VARIANT IRAN TYPE A GLU-1162.
RX   PubMed=8096518;
RA   Cama A., de la Luz Sierra M., Quon M.J., Ottini L., Gorden P.,
RA   Taylor S.I.;
RT   "Substitution of glutamic acid for alanine 1135 in the putative
RT   'catalytic loop' of the tyrosine kinase domain of the human insulin
RT   receptor. A mutation that impairs proteolytic processing into subunits
RT   and inhibits receptor tyrosine kinase activity.";
RL   J. Biol. Chem. 268:8060-8069(1993).
RN   [92]
RP   VARIANT IRAN TYPE A VAL-409.
RX   PubMed=8388389;
RA   Lebrun C., Baron V., Kaliman P., Gautier N., Dolais-Kitabgi J.,
RA   Taylor S.I., Accili D., van Obberghen E.;
RT   "Antibodies to the extracellular receptor domain restore the hormone-
RT   insensitive kinase and conformation of the mutant insulin receptor
RT   valine 382.";
RL   J. Biol. Chem. 268:11272-11277(1993).
RN   [93]
RP   VARIANT LEPRCH MET-146.
RX   PubMed=8326490; DOI=10.1136/jmg.30.6.470;
RA   Al-Gazali L.I., Khalil M., Devadas K.;
RT   "A syndrome of insulin resistance resembling leprechaunism in five
RT   sibs of consanguineous parents.";
RL   J. Med. Genet. 30:470-475(1993).
RN   [94]
RP   VARIANT LEPRCH PRO-113.
RX   PubMed=8419945; DOI=10.1073/pnas.90.1.60;
RA   Longo N., Langley S.D., Griffin L.D., Elsas L.J.;
RT   "Activation of glucose transport by a natural mutation in the human
RT   insulin receptor.";
RL   Proc. Natl. Acad. Sci. U.S.A. 90:60-64(1993).
RN   [95]
RP   VARIANT IRAN TYPE A GLN-1201.
RX   PubMed=8288049; DOI=10.2337/diab.43.2.247;
RA   Moller D.E., Cohen O., Yamaguchi Y., Assiz R., Grigorescu F.,
RA   Eberle A., Morrow L.A., Moses A.C., Flier J.S.;
RT   "Prevalence of mutations in the insulin receptor gene in subjects with
RT   features of the type A syndrome of insulin resistance.";
RL   Diabetes 43:247-255(1994).
RN   [96]
RP   VARIANT RMS SYNDROME LEU-350, VARIANTS IRAN TYPE A LEU-1205 AND
RP   GLN-1378, AND VARIANT MET-1012.
RX   PubMed=8314008; DOI=10.2337/diab.43.3.357;
RA   Krook A., Kumar S., Laing I., Boulton A.J., Wass J.A., O'Rahilly S.;
RT   "Molecular scanning of the insulin receptor gene in syndromes of
RT   insulin resistance.";
RL   Diabetes 43:357-368(1994).
RN   [97]
RP   CHARACTERIZATION OF VARIANT IRAN TYPE A GLN-1201.
RX   PubMed=8082780; DOI=10.1016/0014-5793(94)00876-0;
RA   Moritz W., Froesch E.R., Boeni-Schnetzler M.;
RT   "Functional properties of a heterozygous mutation (Arg1174-->Gln) in
RT   the tyrosine kinase domain of the insulin receptor from a type A
RT   insulin resistant patient.";
RL   FEBS Lett. 351:276-280(1994).
RN   [98]
RP   VARIANT LEPRCH SER-439.
RX   PubMed=8188715;
RA   van der Vorm E.R., Kuipers A., Kielkopf-Renner S., Krans H.M.J.,
RA   Moller W., Maassen J.A.;
RT   "A mutation in the insulin receptor that impairs proreceptor
RT   processing but not insulin binding.";
RL   J. Biol. Chem. 269:14297-14302(1994).
RN   [99]
RP   CHARACTERIZATION OF VARIANTS IRAN TYPE A ASP-1206 AND LEU-1220.
RX   PubMed=7983039;
RA   Imamura T., Takata Y., Sasaoka T., Takada Y., Morioka H., Haruta T.,
RA   Sawa T., Iwanishi M., Hu Y.G., Suzuki Y., Hamada J., Kobayashi M.;
RT   "Two naturally occurring mutations in the kinase domain of insulin
RT   receptor accelerate degradation of the insulin receptor and impair the
RT   kinase activity.";
RL   J. Biol. Chem. 269:31019-31027(1994).
RN   [100]
RP   VARIANT LEPRCH MET-146.
RX   PubMed=7815442; DOI=10.1136/jmg.31.9.715;
RA   Hone J., Accili D., al-Gazali L.I., Lestringant G., Orban T.,
RA   Taylor S.I.;
RT   "Homozygosity for a new mutation (Ile119-->Met) in the insulin
RT   receptor gene in five sibs with familial insulin resistance.";
RL   J. Med. Genet. 31:715-716(1994).
RN   [101]
RP   VARIANT NIDDM ALA-858, AND VARIANT CYS-1361.
RX   PubMed=7657032; DOI=10.2337/diab.44.9.1081;
RA   Kan M., Kanai F., Iida M., Jinnouchi H., Todaka M., Imanaka T.,
RA   Ito K., Nishioka Y., Ohnishi T., Kamohara S., Hayashi H., Murakami T.,
RA   Kagawa S., Sano H., Hashimoto N., Yoshida S., Makino H., Ebina Y.;
RT   "Frequency of mutations of insulin receptor gene in Japanese patients
RT   with NIDDM.";
RL   Diabetes 44:1081-1086(1995).
RN   [102]
RP   VARIANT LEPRCH ASN-308 DEL.
RX   PubMed=7538143; DOI=10.1210/jcem.80.5.7538143;
RA   Longo N., Langley S.D., Griffin L.D., Elsas L.J.;
RT   "Two mutations in the insulin receptor gene of a patient with
RT   leprechaunism: application to prenatal diagnosis.";
RL   J. Clin. Endocrinol. Metab. 80:1496-1501(1995).
RN   [103]
RP   VARIANT PHE-1023.
RX   PubMed=8890729; DOI=10.1530/eje.0.1350357;
RA   Moritz W., Boeni-Schnetzler M., Stevens W., Froesch E.R., Levy J.R.;
RT   "In-frame exon 2 deletion in insulin receptor RNA in a family with
RT   extreme insulin resistance in association with defective insulin
RT   binding: a case report.";
RL   Eur. J. Endocrinol. 135:357-363(1996).
RN   [104]
RP   VARIANT LEPRCH ASN-308 DEL.
RX   PubMed=8636294; DOI=10.1210/jc.81.2.719;
RA   Desbois-Mouthon C., Sert-Langeron C., Magre J., Oreal E., Blivet M.J.,
RA   Flori E., Besmond C., Capeau J., Caron M.;
RT   "Deletion of Asn281 in the alpha-subunit of the human insulin receptor
RT   causes constitutive activation of the receptor and insulin
RT   desensitization.";
RL   J. Clin. Endocrinol. Metab. 81:719-727(1996).
RN   [105]
RP   VARIANT MET-1012.
RX   PubMed=9199575; DOI=10.1086/515464;
RA   Hansen L., Hansen T., Clausen J.O., Echwald S.M., Urhammer S.A.,
RA   Rasmussen S.K., Pedersen O.;
RT   "The Val985Met insulin-receptor variant in the Danish Caucasian
RT   population: lack of associations with non-insulin-dependent diabetes
RT   mellitus or insulin resistance.";
RL   Am. J. Hum. Genet. 60:1532-1535(1997).
RN   [106]
RP   VARIANTS IRAN TYPE A GLY-86 AND PRO-89.
RX   PubMed=9175790; DOI=10.1006/bbrc.1997.6695;
RA   Rouard M., Macari F., Bouix O., Lautier C., Brun J.F., Lefebvre P.,
RA   Renard E., Bringer J., Jaffiol C., Grigorescu F.;
RT   "Identification of two novel insulin receptor mutations, Asp59Gly and
RT   Leu62Pro, in type A syndrome of extreme insulin resistance.";
RL   Biochem. Biophys. Res. Commun. 234:764-768(1997).
RN   [107]
RP   CHARACTERIZATION OF VARIANT LEPRCH MET-937.
RX   PubMed=9299395; DOI=10.1006/bbrc.1997.7181;
RA   Kadowaki H., Takahashi Y., Ando A., Momomura K., Kaburagi Y.,
RA   Quin J.D., MacCuish A.C., Koda N., Fukushima Y., Taylor S.I.,
RA   Akanuma Y., Yazaki Y., Kadowaki T.;
RT   "Four mutant alleles of the insulin receptor gene associated with
RT   genetic syndromes of extreme insulin resistance.";
RL   Biochem. Biophys. Res. Commun. 237:516-520(1997).
RN   [108]
RP   VARIANTS LEPRCH TRP-1119 AND LYS-1206.
RX   PubMed=9249867;
RX   DOI=10.1002/(SICI)1097-0223(199707)17:7<657::AID-PD132>3.3.CO;2-#;
RA   Desbois-Mouthon C., Girodon E., Ghanem N., Caron M., Pennerath A.,
RA   Conteville P., Magre J., Besmond C., Goossens M., Capeau J.,
RA   Amselem S.;
RT   "Molecular analysis of the insulin receptor gene for prenatal
RT   diagnosis of leprechaunism in two families.";
RL   Prenat. Diagn. 17:657-663(1997).
RN   [109]
RP   VARIANTS LEPRCH TYR-301 AND TRP-1201.
RX   PubMed=9703342; DOI=10.2337/diab.47.8.1362;
RA   Whitehead J.P., Soos M.A., Jackson R., Tasic V., Kocova M.,
RA   O'Rahilly S.;
RT   "Multiple molecular mechanisms of insulin receptor dysfunction in a
RT   patient with Donohue syndrome.";
RL   Diabetes 47:1362-1364(1998).
RN   [110]
RP   VARIANTS RMS THR-1143 AND TRP-1158.
RX   PubMed=10443650; DOI=10.1210/jc.84.8.2623;
RA   Longo N., Wang Y., Pasquali M.;
RT   "Progressive decline in insulin levels in Rabson-Mendenhall
RT   syndrome.";
RL   J. Clin. Endocrinol. Metab. 84:2623-2629(1999).
RN   [111]
RP   VARIANTS IRAN TYPE A LEU-167 AND VAL-1055.
RX   PubMed=10733238; DOI=10.1034/j.1399-0004.2000.570110.x;
RA   Rique S., Nogues C., Ibanez L., Marcos M.V., Ferragut J.,
RA   Carrascosa A., Potau N.;
RT   "Identification of three novel mutations in the insulin receptor gene
RT   in type A insulin resistant patients.";
RL   Clin. Genet. 57:67-69(2000).
RN   [112]
RP   VARIANT IRAN TYPE A TYR-280.
RX   PubMed=11260230; DOI=10.1034/j.1399-0004.2001.590309.x;
RA   Osawa H., Nishimiya T., Ochi M., Niiya T., Onuma H., Kitamuro F.,
RA   Kaino Y., Kida K., Makino H.;
RT   "Identification of novel C253Y missense and Y864X nonsense mutations
RT   in the insulin receptor gene in type A insulin-resistant patients.";
RL   Clin. Genet. 59:194-197(2001).
RN   [113]
RP   VARIANT IRAN TYPE A CYS-279.
RX   PubMed=12107746; DOI=10.1007/s00125-002-0798-5;
RA   Hamer I., Foti M., Emkey R., Cordier-Bussat M., Philippe J.,
RA   De Meyts P., Maeder C., Kahn C.R., Carpentier J.-L.;
RT   "An arginine to cysteine(252) mutation in insulin receptors from a
RT   patient with severe insulin resistance inhibits receptor
RT   internalisation but preserves signalling events.";
RL   Diabetologia 45:657-667(2002).
RN   [114]
RP   CHARACTERIZATION OF VARIANTS LEPRCH PRO-113; VAL-119; ASN-308 DEL;
RP   THR-925 AND TRP-926, AND VARIANTS RMS THR-997; THR-1143; TRP-1158 AND
RP   TRP-1201.
RX   PubMed=12023989; DOI=10.1093/hmg/11.12.1465;
RA   Longo N., Wang Y., Smith S.A., Langley S.D., DiMeglio L.A.,
RA   Giannella-Neto D.;
RT   "Genotype-phenotype correlation in inherited severe insulin
RT   resistance.";
RL   Hum. Mol. Genet. 11:1465-1475(2002).
RN   [115]
RP   VARIANT LEPRCH VAL-362 DEL.
RX   PubMed=12538626; DOI=10.1210/en.2002-220815;
RA   George S., Johansen A., Soos M.A., Mortensen H., Gammeltoft S.,
RA   Saudek V., Siddle K., Hansen L., O'Rahilly S.;
RT   "Deletion of V335 from the L2 domain of the insulin receptor results
RT   in a conformationally abnormal receptor that is unable to bind insulin
RT   and causes Donohue's syndrome in a human subject.";
RL   Endocrinology 144:631-637(2003).
RN   [116]
RP   VARIANT IRAN TYPE A HIS-279, VARIANTS LEPRCH GLN-120; LEU-350; ASP-458
RP   AND TRP-1119, CHARACTERIZATION OF VARIANT IRAN TYPE A HIS-279, AND
RP   CHARACTERIZATION OF VARIANTS LEPRCH GLN-120 AND ASP-458.
RX   PubMed=12970295; DOI=10.1210/jc.2003-030034;
RA   Maassen J.A., Tobias E.S., Kayserilli H., Tukel T., Yuksel-Apak M.,
RA   D'Haens E., Kleijer W.J., Fery F., van der Zon G.C.M.;
RT   "Identification and functional assessment of novel and known insulin
RT   receptor mutations in five patients with syndromes of severe insulin
RT   resistance.";
RL   J. Clin. Endocrinol. Metab. 88:4251-4257(2003).
RN   [117]
RP   VARIANT HHF5 GLN-1201.
RX   PubMed=15161766; DOI=10.2337/diabetes.53.6.1592;
RA   Hoejlund K., Hansen T., Lajer M., Henriksen J.E., Levin K.,
RA   Lindholm J., Pedersen O., Bech-Nielsen H.;
RT   "A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia
RT   linked to a mutation in the human insulin receptor gene.";
RL   Diabetes 53:1592-1598(2004).
RN   [118]
RP   VARIANTS RMS ARG-236 AND SER-386, AND CHARACTERIZATION OF VARIANTS RMS
RP   ARG-236 AND SER-386.
RX   PubMed=17201797; DOI=10.1111/j.1365-2265.2006.02678.x;
RA   Tuthill A., Semple R.K., Day R., Soos M.A., Sweeney E., Seymour P.J.,
RA   Didi M., O'Rahilly S.;
RT   "Functional characterization of a novel insulin receptor mutation
RT   contributing to Rabson-Mendenhall syndrome.";
RL   Clin. Endocrinol. (Oxf.) 66:21-26(2007).
RN   [119]
RP   VARIANTS [LARGE SCALE ANALYSIS] ARG-228; ARG-695; SER-811; MET-1012;
RP   VAL-1065 AND ALA-1282.
RX   PubMed=17344846; DOI=10.1038/nature05610;
RA   Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA   Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA   O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA   Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA   Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA   Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA   Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA   West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA   Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA   DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA   Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA   Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT   "Patterns of somatic mutation in human cancer genomes.";
RL   Nature 446:153-158(2007).
CC   -!- FUNCTION: Receptor tyrosine kinase which mediates the pleiotropic
CC       actions of insulin. Binding of insulin leads to phosphorylation of
CC       several intracellular substrates, including, insulin receptor
CC       substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling
CC       intermediates. Each of these phosphorylated proteins serve as
CC       docking proteins for other signaling proteins that contain Src-
CC       homology-2 domains (SH2 domain) that specifically recognize
CC       different phosphotyrosines residues, including the p85 regulatory
CC       subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to
CC       the activation of two main signaling pathways: the PI3K-AKT/PKB
CC       pathway, which is responsible for most of the metabolic actions of
CC       insulin, and the Ras-MAPK pathway, which regulates expression of
CC       some genes and cooperates with the PI3K pathway to control cell
CC       growth and differentiation. Binding of the SH2 domains of PI3K to
CC       phosphotyrosines on IRS1 leads to the activation of PI3K and the
CC       generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3),
CC       a lipid second messenger, which activates several PIP3-dependent
CC       serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB.
CC       The net effect of this pathway is to produce a translocation of
CC       the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to
CC       the cell membrane to facilitate glucose transport. Moreover, upon
CC       insulin stimulation, activated AKT/PKB is responsible for: anti-
CC       apoptotic effect of insulin by inducing phosphorylation of BAD;
CC       regulates the expression of gluconeogenic and lipogenic enzymes by
CC       controlling the activity of the winged helix or forkhead (FOX)
CC       class of transcription factors. Another pathway regulated by PI3K-
CC       AKT/PKB activation is mTORC1 signaling pathway which regulates
CC       cell growth and metabolism and integrates signals from insulin.
CC       AKT mediates insulin-stimulated protein synthesis by
CC       phosphorylating TSC2 thereby activating mTORC1 pathway. The
CC       Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell
CC       growth, survival and cellular differentiation of insulin.
CC       Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the
CC       activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to
CC       binding insulin, the insulin receptor can bind insulin-like growth
CC       factors (IGFI and IGFII). Isoform Short has a higher affinity for
CC       IGFII binding. When present in a hybrid receptor with IGF1R, binds
CC       IGF1. PubMed:12138094 shows that hybrid receptors composed of
CC       IGF1R and INSR isoform Long are activated with a high affinity by
CC       IGF1, with low affinity by IGF2 and not significantly activated by
CC       insulin, and that hybrid receptors composed of IGF1R and INSR
CC       isoform Short are activated by IGF1, IGF2 and insulin. In
CC       contrast, PubMed:16831875 shows that hybrid receptors composed of
CC       IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R
CC       and INSR isoform Short have similar binding characteristics, both
CC       bind IGF1 and have a low affinity for insulin.
CC       {ECO:0000269|PubMed:12138094, ECO:0000269|PubMed:16314505,
CC       ECO:0000269|PubMed:16831875, ECO:0000269|PubMed:8257688,
CC       ECO:0000269|PubMed:8276809, ECO:0000269|PubMed:8452530,
CC       ECO:0000269|PubMed:9428692}.
CC   -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
CC       [protein]-L-tyrosine phosphate. {ECO:0000255|PROSITE-
CC       ProRule:PRU10028, ECO:0000269|PubMed:11124964,
CC       ECO:0000269|PubMed:11598120, ECO:0000269|PubMed:12707268,
CC       ECO:0000269|PubMed:18278056, ECO:0000269|PubMed:19056263,
CC       ECO:0000269|PubMed:19071018, ECO:0000269|PubMed:19394223,
CC       ECO:0000269|PubMed:9312016}.
CC   -!- ENZYME REGULATION: Activated in response to insulin.
CC       Autophosphorylation activates the kinase activity. PTPN1, PTPRE
CC       and PTPRF dephosphorylate important tyrosine residues, thereby
CC       reducing INSR activity. Inhibited by ENPP1. GRB10 and GRB14
CC       inhibit the catalytic activity of the INSR, they block access of
CC       substrates to the activated receptor. SOCS1 and SOCS3 act as
CC       negative regulators of INSR activity, they bind to the activated
CC       INRS and interfere with the phosphorylation of INSR substrates.
CC       {ECO:0000269|PubMed:10615944, ECO:0000269|PubMed:11598120,
CC       ECO:0000269|PubMed:11726652, ECO:0000269|PubMed:12493740,
CC       ECO:0000269|PubMed:2211730}.
CC   -!- SUBUNIT: Tetramer of 2 alpha and 2 beta chains linked by disulfide
CC       bonds. The alpha chains carry the insulin-binding regions, while
CC       the beta chains carry the kinase domain. Forms a hybrid receptor
CC       with IGF1R, the hybrid is a tetramer consisting of 1 alpha chain
CC       and 1 beta chain of INSR and 1 alpha chain and 1 beta chain of
CC       IGF1R. Interacts with SORBS1 but dissociates from it following
CC       insulin stimulation. Binds SH2B2. Activated form of INSR interacts
CC       (via Tyr-999) with the PTB/PID domains of IRS1 and SHC1. The
CC       sequences surrounding the phosphorylated NPXY motif contribute
CC       differentially to either IRS1 or SHC1 recognition. Interacts (via
CC       tyrosines in the C-terminus) with IRS2 (via PTB domain and 591-786
CC       AA); the 591-786 would be the primary anchor of IRS2 to INSR while
CC       the PTB domain would have a stabilizing action on the interaction
CC       with INSR. Interacts with the SH2 domains of the 85 kDa regulatory
CC       subunit of PI3K (PIK3R1) in vitro, when autophosphorylated on
CC       tyrosine residues. Interacts with SOCS7. Interacts (via the
CC       phosphorylated Tyr-999), with SOCS3. Interacts (via the
CC       phosphorylated Tyr-1185, Tyr-1189, Tyr-1190) with SOCS1. Interacts
CC       with CAV2 (tyrosine-phosphorylated form); the interaction is
CC       increased with 'Tyr-27'phosphorylation of CAV2 (By similarity).
CC       Interacts with ARRB2 (By similarity). Interacts with GRB10; this
CC       interaction blocks the association between IRS1/IRS2 and INSR,
CC       significantly reduces insulin-stimulated tyrosine phosphorylation
CC       of IRS1 and IRS2 and thus decreases insulin signaling. Interacts
CC       with GRB7. Interacts with PDPK1. Interacts (via Tyr-1190) with
CC       GRB14 (via BPS domain); this interaction protects the tyrosines in
CC       the activation loop from dephosphorylation, but promotes
CC       dephosphorylation of Tyr-999, this results in decreased
CC       interaction with, and phosphorylation of, IRS1. Interacts (via
CC       subunit alpha) with ENPP1 (via 485-599 AA); this interaction
CC       blocks autophosphorylation. Interacts with PTPRE; this interaction
CC       is dependent of Tyr-1185, Tyr-1189 and Tyr-1190 of the INSR.
CC       Interacts with STAT5B (via SH2 domain). Interacts with PTPRF.
CC       {ECO:0000250, ECO:0000269|PubMed:10615944,
CC       ECO:0000269|PubMed:10803466, ECO:0000269|PubMed:11124964,
CC       ECO:0000269|PubMed:11374898, ECO:0000269|PubMed:11726652,
CC       ECO:0000269|PubMed:12493740, ECO:0000269|PubMed:14690593,
CC       ECO:0000269|PubMed:16127460, ECO:0000269|PubMed:16246733,
CC       ECO:0000269|PubMed:16271887, ECO:0000269|PubMed:16314505,
CC       ECO:0000269|PubMed:16957736, ECO:0000269|PubMed:18278056,
CC       ECO:0000269|PubMed:18767165, ECO:0000269|PubMed:19056263,
CC       ECO:0000269|PubMed:19071018, ECO:0000269|PubMed:19394223,
CC       ECO:0000269|PubMed:2211730, ECO:0000269|PubMed:23302862,
CC       ECO:0000269|PubMed:7537849, ECO:0000269|PubMed:7559478,
CC       ECO:0000269|PubMed:8276809, ECO:0000269|PubMed:8995282,
CC       ECO:0000269|PubMed:8999839, ECO:0000269|PubMed:9312016,
CC       ECO:0000269|PubMed:9428692}.
CC   -!- INTERACTION:
CC       Q99490:AGAP2; NbExp=2; IntAct=EBI-475899, EBI-2361824;
CC       P22413:ENPP1; NbExp=2; IntAct=EBI-475899, EBI-3197846;
CC       Q13322:GRB10; NbExp=3; IntAct=EBI-475899, EBI-80275;
CC       P05019:IGF1; NbExp=4; IntAct=EBI-475899, EBI-7902275;
CC       P01317:INS (xeno); NbExp=5; IntAct=EBI-475899, EBI-3989070;
CC       P35568:IRS1; NbExp=3; IntAct=EBI-475899, EBI-517592;
CC       P35570:Irs1 (xeno); NbExp=5; IntAct=EBI-475899, EBI-520230;
CC       P27986:PIK3R1; NbExp=3; IntAct=EBI-475899, EBI-79464;
CC       P19174:PLCG1; NbExp=9; IntAct=EBI-475899, EBI-79387;
CC       P18031:PTPN1; NbExp=33; IntAct=EBI-475899, EBI-968788;
CC       Q06124:PTPN11; NbExp=2; IntAct=EBI-475899, EBI-297779;
CC       Q9NRF2:SH2B1; NbExp=6; IntAct=EBI-475899, EBI-310491;
CC       P29353:SHC1; NbExp=2; IntAct=EBI-475899, EBI-78835;
CC   -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC       protein.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=Long; Synonyms=HIR-B;
CC         IsoId=P06213-1; Sequence=Displayed;
CC       Name=Short; Synonyms=HIR-A;
CC         IsoId=P06213-2; Sequence=VSP_002898;
CC   -!- TISSUE SPECIFICITY: Isoform Long and isoform Short are
CC       predominantly expressed in tissue targets of insulin metabolic
CC       effects: liver, adipose tissue and skeletal muscle but are also
CC       expressed in the peripheral nerve, kidney, pulmonary alveoli,
CC       pancreatic acini, placenta vascular endothelium, fibroblasts,
CC       monocytes, granulocytes, erythrocytes and skin. Isoform Short is
CC       preferentially expressed in fetal cells such as fetal fibroblasts,
CC       muscle, liver and kidney. Found as a hybrid receptor with IGF1R in
CC       muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma,
CC       fibroblasts, spleen and placenta (at protein level). Overexpressed
CC       in several tumors, including breast, colon, lung, ovary, and
CC       thyroid carcinomas. {ECO:0000269|PubMed:10207053,
CC       ECO:0000269|PubMed:2369896, ECO:0000269|PubMed:9202395,
CC       ECO:0000269|PubMed:9355755}.
CC   -!- DOMAIN: The tetrameric insulin receptor binds insulin via non-
CC       identical regions from two alpha chains, primarily via the C-
CC       terminal region of the first INSR alpha chain. Residues from the
CC       leucine-rich N-terminus of the other INSR alpha chain also
CC       contribute to this insulin binding site. A secondary insulin-
CC       binding site is formed by residues at the junction of fibronectin
CC       type-III domain 1 and 2. {ECO:0000269|PubMed:16957736,
CC       ECO:0000269|PubMed:19459609, ECO:0000269|PubMed:23302862}.
CC   -!- PTM: After being transported from the endoplasmic reticulum to the
CC       Golgi apparatus, the single glycosylated precursor is further
CC       glycosylated and then cleaved, followed by its transport to the
CC       plasma membrane. {ECO:0000269|PubMed:1472036,
CC       ECO:0000269|PubMed:16894147, ECO:0000269|PubMed:19159218,
CC       ECO:0000269|PubMed:19349973, ECO:0000269|PubMed:23302862,
CC       ECO:0000269|PubMed:2983222}.
CC   -!- PTM: Autophosphorylated on tyrosine residues in response to
CC       insulin. Phosphorylation of Tyr-999 is required for binding to
CC       IRS1, SHC1 and STAT5B. Dephosphorylated by PTPRE at Tyr-999, Tyr-
CC       1185, Tyr-1189 and Tyr-1190. Dephosphorylated by PTPRF and PTPN1.
CC       Dephosphorylated by PTPN2; down-regulates insulin-induced
CC       signaling. {ECO:0000269|PubMed:10734133,
CC       ECO:0000269|PubMed:12612081, ECO:0000269|PubMed:14690593,
CC       ECO:0000269|PubMed:16246733, ECO:0000269|PubMed:16271887,
CC       ECO:0000269|PubMed:18278056, ECO:0000269|PubMed:18669648,
CC       ECO:0000269|PubMed:18767165, ECO:0000269|PubMed:3166375,
CC       ECO:0000269|PubMed:9312016}.
CC   -!- DISEASE: Rabson-Mendenhall syndrome (RMS) [MIM:262190]: Severe
CC       insulin resistance syndrome characterized by insulin-resistant
CC       diabetes mellitus with pineal hyperplasia and somatic
CC       abnormalities. Typical features include coarse, senile-appearing
CC       facies, dental and skin abnormalities, abdominal distension, and
CC       phallic enlargement. Inheritance is autosomal recessive.
CC       {ECO:0000269|PubMed:10443650, ECO:0000269|PubMed:12023989,
CC       ECO:0000269|PubMed:17201797, ECO:0000269|PubMed:2365819,
CC       ECO:0000269|PubMed:8314008}. Note=The disease is caused by
CC       mutations affecting the gene represented in this entry.
CC   -!- DISEASE: Leprechaunism (LEPRCH) [MIM:246200]: Represents the most
CC       severe form of insulin resistance syndrome, characterized by
CC       intrauterine and postnatal growth retardation and death in early
CC       infancy. Inheritance is autosomal recessive.
CC       {ECO:0000269|PubMed:12538626, ECO:0000269|PubMed:12970295,
CC       ECO:0000269|PubMed:1607067, ECO:0000269|PubMed:1730625,
CC       ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:2479553,
CC       ECO:0000269|PubMed:2834824, ECO:0000269|PubMed:7538143,
CC       ECO:0000269|PubMed:7815442, ECO:0000269|PubMed:8188715,
CC       ECO:0000269|PubMed:8326490, ECO:0000269|PubMed:8419945,
CC       ECO:0000269|PubMed:8636294, ECO:0000269|PubMed:9249867,
CC       ECO:0000269|PubMed:9703342}. Note=The disease is caused by
CC       mutations affecting the gene represented in this entry.
CC   -!- DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM)
CC       [MIM:125853]: A multifactorial disorder of glucose homeostasis
CC       caused by a lack of sensitivity to the body's own insulin.
CC       Affected individuals usually have an obese body habitus and
CC       manifestations of a metabolic syndrome characterized by diabetes,
CC       insulin resistance, hypertension and hypertriglyceridemia. The
CC       disease results in long-term complications that affect the eyes,
CC       kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:1470163,
CC       ECO:0000269|PubMed:1607076, ECO:0000269|PubMed:7657032}. Note=The
CC       gene represented in this entry may be involved in disease
CC       pathogenesis.
CC   -!- DISEASE: Familial hyperinsulinemic hypoglycemia 5 (HHF5)
CC       [MIM:609968]: Familial hyperinsulinemic hypoglycemia [MIM:256450],
CC       also referred to as congenital hyperinsulinism, nesidioblastosis,
CC       or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is
CC       the most common cause of persistent hypoglycemia in infancy and is
CC       due to defective negative feedback regulation of insulin secretion
CC       by low glucose levels. {ECO:0000269|PubMed:15161766}. Note=The
CC       disease is caused by mutations affecting the gene represented in
CC       this entry.
CC   -!- DISEASE: Insulin-resistant diabetes mellitus with acanthosis
CC       nigricans type A (IRAN type A) [MIM:610549]: Characterized by the
CC       association of severe insulin resistance (manifested by marked
CC       hyperinsulinemia and a failure to respond to exogenous insulin)
CC       with the skin lesion acanthosis nigricans and ovarian
CC       hyperandrogenism in adolescent female subjects. Women frequently
CC       present with hirsutism, acne, amenorrhea or oligomenorrhea, and
CC       virilization. This syndrome is different from the type B that has
CC       been demonstrated to be secondary to the presence of circulating
CC       autoantibodies against the insulin receptor.
CC       {ECO:0000269|PubMed:10733238, ECO:0000269|PubMed:11260230,
CC       ECO:0000269|PubMed:12107746, ECO:0000269|PubMed:12970295,
CC       ECO:0000269|PubMed:1563582, ECO:0000269|PubMed:1963473,
CC       ECO:0000269|PubMed:2002058, ECO:0000269|PubMed:2168397,
CC       ECO:0000269|PubMed:2365819, ECO:0000269|PubMed:2544998,
CC       ECO:0000269|PubMed:3283938, ECO:0000269|PubMed:8243830,
CC       ECO:0000269|PubMed:8288049, ECO:0000269|PubMed:8314008,
CC       ECO:0000269|PubMed:8388389, ECO:0000269|PubMed:9175790}. Note=The
CC       disease is caused by mutations affecting the gene represented in
CC       this entry.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC       kinase family. Insulin receptor subfamily. {ECO:0000255|PROSITE-
CC       ProRule:PRU00159}.
CC   -!- SIMILARITY: Contains 3 fibronectin type-III domains.
CC       {ECO:0000255|PROSITE-ProRule:PRU00316}.
CC   -!- SIMILARITY: Contains 1 protein kinase domain.
CC       {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC   -!- WEB RESOURCE: Name=Wikipedia; Note=Insulin receptor entry;
CC       URL="http://en.wikipedia.org/wiki/Insulin_receptor";
CC   -----------------------------------------------------------------------
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DR   EMBL; M10051; AAA59174.1; -; mRNA.
DR   EMBL; X02160; CAA26096.1; -; mRNA.
DR   EMBL; M32972; AAA59452.1; -; Genomic_DNA.
DR   EMBL; M23100; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32823; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32824; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32825; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32826; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32827; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32828; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32829; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32830; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32831; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32832; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32833; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32834; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32835; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32836; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32837; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32838; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32839; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32840; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32841; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; M32842; AAA59452.1; JOINED; Genomic_DNA.
DR   EMBL; AC010311; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC010526; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC010606; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AC125387; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC117172; AAI17173.1; -; mRNA.
DR   EMBL; J03466; AAA59175.1; -; Genomic_DNA.
DR   EMBL; J05043; AAA59190.1; -; Genomic_DNA.
DR   EMBL; M76592; AAC37604.1; -; Genomic_DNA.
DR   EMBL; AB208861; BAD92098.1; -; mRNA.
DR   EMBL; M24555; AAA59178.1; -; mRNA.
DR   EMBL; M29929; AAA59176.1; -; Genomic_DNA.
DR   EMBL; M29930; AAA59177.1; -; Genomic_DNA.
DR   EMBL; M27197; AAA86791.1; -; Genomic_DNA.
DR   EMBL; M27195; AAA86791.1; JOINED; Genomic_DNA.
DR   CCDS; CCDS12176.1; -. [P06213-1]
DR   CCDS; CCDS42487.1; -. [P06213-2]
DR   PIR; A37348; INHUR.
DR   RefSeq; NP_000199.2; NM_000208.2. [P06213-1]
DR   RefSeq; NP_001073285.1; NM_001079817.1. [P06213-2]
DR   UniGene; Hs.465744; -.
DR   PDB; 1GAG; X-ray; 2.70 A; A=1005-1310.
DR   PDB; 1I44; X-ray; 2.40 A; A=1005-1310.
DR   PDB; 1IR3; X-ray; 1.90 A; A=1005-1310.
DR   PDB; 1IRK; X-ray; 2.10 A; A=1005-1310.
DR   PDB; 1P14; X-ray; 1.90 A; A=1005-1310.
DR   PDB; 1RQQ; X-ray; 2.60 A; A/B=1005-1310.
DR   PDB; 2AUH; X-ray; 3.20 A; A=1005-1310.
DR   PDB; 2B4S; X-ray; 2.30 A; B/D=1005-1310.
DR   PDB; 2DTG; X-ray; 3.80 A; E=28-955.
DR   PDB; 2HR7; X-ray; 2.32 A; A/B=28-512.
DR   PDB; 2MFR; NMR; -; A=940-988.
DR   PDB; 2Z8C; X-ray; 3.25 A; A=1008-1310.
DR   PDB; 3BU3; X-ray; 1.65 A; A=1005-1310.
DR   PDB; 3BU5; X-ray; 2.10 A; A=1005-1310.
DR   PDB; 3BU6; X-ray; 1.95 A; A=1005-1310.
DR   PDB; 3EKK; X-ray; 2.10 A; A=1005-1310.
DR   PDB; 3EKN; X-ray; 2.20 A; A=1005-1310.
DR   PDB; 3ETA; X-ray; 2.60 A; A/B=1017-1322.
DR   PDB; 3LOH; X-ray; 3.80 A; E=28-956.
DR   PDB; 3W11; X-ray; 3.90 A; E=28-337, F=731-744.
DR   PDB; 3W12; X-ray; 4.30 A; E=28-337, F=731-744.
DR   PDB; 3W13; X-ray; 4.30 A; E=28-337, F=724-744.
DR   PDB; 3W14; X-ray; 4.40 A; E/F=28-746.
DR   PDB; 4IBM; X-ray; 1.80 A; A/B=1005-1310.
DR   PDB; 4OGA; X-ray; 3.50 A; E=28-337, F=731-744.
DR   PDBsum; 1GAG; -.
DR   PDBsum; 1I44; -.
DR   PDBsum; 1IR3; -.
DR   PDBsum; 1IRK; -.
DR   PDBsum; 1P14; -.
DR   PDBsum; 1RQQ; -.
DR   PDBsum; 2AUH; -.
DR   PDBsum; 2B4S; -.
DR   PDBsum; 2DTG; -.
DR   PDBsum; 2HR7; -.
DR   PDBsum; 2MFR; -.
DR   PDBsum; 2Z8C; -.
DR   PDBsum; 3BU3; -.
DR   PDBsum; 3BU5; -.
DR   PDBsum; 3BU6; -.
DR   PDBsum; 3EKK; -.
DR   PDBsum; 3EKN; -.
DR   PDBsum; 3ETA; -.
DR   PDBsum; 3LOH; -.
DR   PDBsum; 3W11; -.
DR   PDBsum; 3W12; -.
DR   PDBsum; 3W13; -.
DR   PDBsum; 3W14; -.
DR   PDBsum; 4IBM; -.
DR   PDBsum; 4OGA; -.
DR   ProteinModelPortal; P06213; -.
DR   SMR; P06213; 31-988, 1009-1339.
DR   BioGrid; 109854; 61.
DR   DIP; DIP-480N; -.
DR   IntAct; P06213; 43.
DR   MINT; MINT-1516246; -.
DR   STRING; 9606.ENSP00000303830; -.
DR   BindingDB; P06213; -.
DR   ChEMBL; CHEMBL1981; -.
DR   DrugBank; DB00071; "Insulin.
DR   DrugBank; DB08914; "Insulin.
DR   DrugBank; DB01306; Insulin Aspart.
DR   DrugBank; DB01307; Insulin Detemir.
DR   DrugBank; DB00047; Insulin Glargine.
DR   DrugBank; DB01309; Insulin Glulisine.
DR   DrugBank; DB00046; Insulin Lispro.
DR   DrugBank; DB00030; Insulin Regular.
DR   DrugBank; DB01277; Mecasermin.
DR   GuidetoPHARMACOLOGY; 1800; -.
DR   PhosphoSite; P06213; -.
DR   DMDM; 308153655; -.
DR   MaxQB; P06213; -.
DR   PaxDb; P06213; -.
DR   PRIDE; P06213; -.
DR   DNASU; 3643; -.
DR   Ensembl; ENST00000302850; ENSP00000303830; ENSG00000171105. [P06213-1]
DR   Ensembl; ENST00000341500; ENSP00000342838; ENSG00000171105. [P06213-2]
DR   GeneID; 3643; -.
DR   KEGG; hsa:3643; -.
DR   UCSC; uc002mgd.1; human. [P06213-1]
DR   UCSC; uc002mge.1; human. [P06213-2]
DR   CTD; 3643; -.
DR   GeneCards; GC19M007112; -.
DR   H-InvDB; HIX0040111; -.
DR   HGNC; HGNC:6091; INSR.
DR   HPA; HPA036302; -.
DR   MIM; 125853; phenotype.
DR   MIM; 147670; gene.
DR   MIM; 246200; phenotype.
DR   MIM; 262190; phenotype.
DR   MIM; 609968; phenotype.
DR   MIM; 610549; phenotype.
DR   neXtProt; NX_P06213; -.
DR   Orphanet; 263458; Hyperinsulinism due to INSR deficiency.
DR   Orphanet; 2297; Insulin-resistance syndrome type A.
DR   Orphanet; 508; Leprechaunism.
DR   Orphanet; 769; Rabson-Mendenhall syndrome.
DR   PharmGKB; PA202; -.
DR   eggNOG; COG0515; -.
DR   GeneTree; ENSGT00760000118818; -.
DR   HOGENOM; HOG000038045; -.
DR   HOVERGEN; HBG006134; -.
DR   InParanoid; P06213; -.
DR   KO; K04527; -.
DR   OMA; CPERVTD; -.
DR   OrthoDB; EOG73RB9N; -.
DR   PhylomeDB; P06213; -.
DR   TreeFam; TF351636; -.
DR   BRENDA; 2.7.10.1; 2681.
DR   Reactome; REACT_1109; Insulin receptor recycling.
DR   Reactome; REACT_1661; SHC activation.
DR   Reactome; REACT_498; Signaling by Insulin receptor.
DR   Reactome; REACT_508; Signal attenuation.
DR   Reactome; REACT_570; IRS activation.
DR   SABIO-RK; P06213; -.
DR   SignaLink; P06213; -.
DR   ChiTaRS; INSR; human.
DR   EvolutionaryTrace; P06213; -.
DR   GeneWiki; Insulin_receptor; -.
DR   GenomeRNAi; 3643; -.
DR   NextBio; 14259; -.
DR   PRO; PR:P06213; -.
DR   Proteomes; UP000005640; Chromosome 19.
DR   Bgee; P06213; -.
DR   CleanEx; HS_INSR; -.
DR   ExpressionAtlas; P06213; baseline and differential.
DR   Genevestigator; P06213; -.
DR   GO; GO:0005901; C:caveola; IDA:BHF-UCL.
DR   GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR   GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR   GO; GO:0005899; C:insulin receptor complex; IMP:BHF-UCL.
DR   GO; GO:0005887; C:integral component of plasma membrane; IDA:BHF-UCL.
DR   GO; GO:0016020; C:membrane; IDA:BHF-UCL.
DR   GO; GO:0005886; C:plasma membrane; IC:BHF-UCL.
DR   GO; GO:0043235; C:receptor complex; IDA:MGI.
DR   GO; GO:0005524; F:ATP binding; IDA:BHF-UCL.
DR   GO; GO:0005525; F:GTP binding; IDA:BHF-UCL.
DR   GO; GO:0043559; F:insulin binding; IDA:UniProtKB.
DR   GO; GO:0043560; F:insulin receptor substrate binding; IPI:UniProtKB.
DR   GO; GO:0005009; F:insulin-activated receptor activity; IDA:UniProtKB.
DR   GO; GO:0031994; F:insulin-like growth factor I binding; IPI:BHF-UCL.
DR   GO; GO:0031995; F:insulin-like growth factor II binding; IPI:BHF-UCL.
DR   GO; GO:0005159; F:insulin-like growth factor receptor binding; IDA:BHF-UCL.
DR   GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; IPI:UniProtKB.
DR   GO; GO:0004713; F:protein tyrosine kinase activity; IMP:UniProtKB.
DR   GO; GO:0051425; F:PTB domain binding; IPI:UniProtKB.
DR   GO; GO:0004716; F:receptor signaling protein tyrosine kinase activity; IDA:BHF-UCL.
DR   GO; GO:0000187; P:activation of MAPK activity; IMP:BHF-UCL.
DR   GO; GO:0032147; P:activation of protein kinase activity; IMP:BHF-UCL.
DR   GO; GO:0032148; P:activation of protein kinase B activity; IDA:BHF-UCL.
DR   GO; GO:0005975; P:carbohydrate metabolic process; IEA:UniProtKB-KW.
DR   GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl.
DR   GO; GO:0032869; P:cellular response to insulin stimulus; IDA:BHF-UCL.
DR   GO; GO:0008544; P:epidermis development; IEA:Ensembl.
DR   GO; GO:0031017; P:exocrine pancreas development; IEA:Ensembl.
DR   GO; GO:0007186; P:G-protein coupled receptor signaling pathway; IDA:BHF-UCL.
DR   GO; GO:0042593; P:glucose homeostasis; IMP:BHF-UCL.
DR   GO; GO:0003007; P:heart morphogenesis; IMP:BHF-UCL.
DR   GO; GO:0008286; P:insulin receptor signaling pathway; IDA:UniProtKB.
DR   GO; GO:0030238; P:male sex determination; IEA:Ensembl.
DR   GO; GO:0038083; P:peptidyl-tyrosine autophosphorylation; IEA:Ensembl.
DR   GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:BHF-UCL.
DR   GO; GO:0030335; P:positive regulation of cell migration; IMP:BHF-UCL.
DR   GO; GO:0008284; P:positive regulation of cell proliferation; IDA:BHF-UCL.
DR   GO; GO:0048639; P:positive regulation of developmental growth; IMP:BHF-UCL.
DR   GO; GO:0045740; P:positive regulation of DNA replication; IMP:BHF-UCL.
DR   GO; GO:0046326; P:positive regulation of glucose import; IDA:BHF-UCL.
DR   GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; IDA:BHF-UCL.
DR   GO; GO:0045821; P:positive regulation of glycolytic process; IMP:BHF-UCL.
DR   GO; GO:0043410; P:positive regulation of MAPK cascade; IMP:BHF-UCL.
DR   GO; GO:0045840; P:positive regulation of mitosis; IMP:BHF-UCL.
DR   GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IMP:BHF-UCL.
DR   GO; GO:0051897; P:positive regulation of protein kinase B signaling; IMP:BHF-UCL.
DR   GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:BHF-UCL.
DR   GO; GO:0060267; P:positive regulation of respiratory burst; IDA:BHF-UCL.
DR   GO; GO:0046777; P:protein autophosphorylation; IMP:UniProtKB.
DR   GO; GO:0051290; P:protein heterotetramerization; IDA:UniProtKB.
DR   GO; GO:0045995; P:regulation of embryonic development; IMP:BHF-UCL.
DR   GO; GO:0006355; P:regulation of transcription, DNA-templated; IMP:BHF-UCL.
DR   GO; GO:0023014; P:signal transduction by phosphorylation; IDA:GOC.
DR   GO; GO:0019087; P:transformation of host cell by virus; IMP:BHF-UCL.
DR   Gene3D; 2.60.40.10; -; 4.
DR   Gene3D; 3.80.20.20; -; 2.
DR   InterPro; IPR003961; FN3_dom.
DR   InterPro; IPR006211; Furin-like_Cys-rich_dom.
DR   InterPro; IPR006212; Furin_repeat.
DR   InterPro; IPR009030; Growth_fac_rcpt_N_dom.
DR   InterPro; IPR013783; Ig-like_fold.
DR   InterPro; IPR011009; Kinase-like_dom.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR000494; rcpt_L-dom.
DR   InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR   InterPro; IPR008266; Tyr_kinase_AS.
DR   InterPro; IPR020635; Tyr_kinase_cat_dom.
DR   InterPro; IPR016246; Tyr_kinase_insulin-like_rcpt.
DR   InterPro; IPR002011; Tyr_kinase_rcpt_2_CS.
DR   Pfam; PF00041; fn3; 1.
DR   Pfam; PF00757; Furin-like; 1.
DR   Pfam; PF07714; Pkinase_Tyr; 1.
DR   Pfam; PF01030; Recep_L_domain; 2.
DR   PIRSF; PIRSF000620; Insulin_receptor; 1.
DR   PRINTS; PR00109; TYRKINASE.
DR   SMART; SM00060; FN3; 3.
DR   SMART; SM00261; FU; 2.
DR   SMART; SM00219; TyrKc; 1.
DR   SUPFAM; SSF49265; SSF49265; 4.
DR   SUPFAM; SSF56112; SSF56112; 1.
DR   SUPFAM; SSF57184; SSF57184; 1.
DR   PROSITE; PS50853; FN3; 2.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR   PROSITE; PS00239; RECEPTOR_TYR_KIN_II; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; ATP-binding;
KW   Carbohydrate metabolism; Cell membrane;
KW   Cleavage on pair of basic residues; Complete proteome;
KW   Diabetes mellitus; Direct protein sequencing; Disease mutation;
KW   Disulfide bond; Glycoprotein; Kinase; Membrane; Nucleotide-binding;
KW   Phosphoprotein; Polymorphism; Receptor; Reference proteome; Repeat;
KW   Signal; Transferase; Transmembrane; Transmembrane helix;
KW   Tyrosine-protein kinase.
FT   SIGNAL        1     27       {ECO:0000269|PubMed:2211730,
FT                                ECO:0000269|PubMed:2983222,
FT                                ECO:0000269|PubMed:8257688}.
FT   CHAIN        28    758       Insulin receptor subunit alpha.
FT                                /FTId=PRO_0000016687.
FT   CHAIN       763   1382       Insulin receptor subunit beta.
FT                                /FTId=PRO_0000016689.
FT   TOPO_DOM     28    758       Extracellular. {ECO:0000305}.
FT   TOPO_DOM    763    956       Extracellular. {ECO:0000305}.
FT   TRANSMEM    957    979       Helical. {ECO:0000255}.
FT   TOPO_DOM    980   1382       Cytoplasmic. {ECO:0000305}.
FT   DOMAIN      624    726       Fibronectin type-III 1.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00316}.
FT   DOMAIN      757    842       Fibronectin type-III 2.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00316}.
FT   DOMAIN      853    947       Fibronectin type-III 3.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00316}.
FT   DOMAIN     1023   1298       Protein kinase. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159}.
FT   NP_BIND    1104   1110       ATP. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159,
FT                                ECO:0000269|PubMed:18278056}.
FT   NP_BIND    1163   1164       ATP. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159,
FT                                ECO:0000269|PubMed:18278056}.
FT   REGION      733    741       Insulin-binding.
FT   REGION      999    999       Important for interaction with IRS1, SHC1
FT                                and STAT5B.
FT   REGION     1361   1364       PIK3R1-binding.
FT   COMPBIAS     28    174       Leu-rich.
FT   COMPBIAS    182    339       Cys-rich.
FT   ACT_SITE   1159   1159       Proton donor/acceptor.
FT                                {ECO:0000269|PubMed:9312016}.
FT   BINDING    1033   1033       ATP. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159,
FT                                ECO:0000269|PubMed:18278056}.
FT   BINDING    1057   1057       ATP. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159,
FT                                ECO:0000269|PubMed:18278056}.
FT   BINDING    1177   1177       ATP. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00159,
FT                                ECO:0000269|PubMed:18278056}.
FT   SITE         66     66       Insulin-binding. {ECO:0000305}.
FT   MOD_RES     400    400       Phosphoserine.
FT                                {ECO:0000269|PubMed:18669648}.
FT   MOD_RES     401    401       Phosphotyrosine.
FT                                {ECO:0000269|PubMed:18669648}.
FT   MOD_RES     407    407       Phosphoserine.
FT                                {ECO:0000269|PubMed:18669648}.
FT   MOD_RES     992    992       Phosphotyrosine; by autocatalysis.
FT                                {ECO:0000305}.
FT   MOD_RES     999    999       Phosphotyrosine; by autocatalysis.
FT                                {ECO:0000305|PubMed:3166375}.
FT   MOD_RES    1011   1011       Phosphotyrosine; by autocatalysis.
FT                                {ECO:0000305}.
FT   MOD_RES    1185   1185       Phosphotyrosine; by autocatalysis.
FT                                {ECO:0000269|PubMed:14690593,
FT                                ECO:0000269|PubMed:16246733,
FT                                ECO:0000269|PubMed:16271887,
FT                                ECO:0000269|PubMed:18278056,
FT                                ECO:0000269|PubMed:18767165,
FT                                ECO:0000269|PubMed:3166375,
FT                                ECO:0000269|PubMed:9312016}.
FT   MOD_RES    1189   1189       Phosphotyrosine; by autocatalysis.
FT                                {ECO:0000269|PubMed:14690593,
FT                                ECO:0000269|PubMed:16246733,
FT                                ECO:0000269|PubMed:16271887,
FT                                ECO:0000269|PubMed:18278056,
FT                                ECO:0000269|PubMed:18767165,
FT                                ECO:0000269|PubMed:3166375,
FT                                ECO:0000269|PubMed:9312016}.
FT   MOD_RES    1190   1190       Phosphotyrosine; by autocatalysis.
FT                                {ECO:0000269|PubMed:14690593,
FT                                ECO:0000269|PubMed:16246733,
FT                                ECO:0000269|PubMed:16271887,
FT                                ECO:0000269|PubMed:18278056,
FT                                ECO:0000269|PubMed:18767165,
FT                                ECO:0000269|PubMed:3166375,
FT                                ECO:0000269|PubMed:9312016}.
FT   MOD_RES    1355   1355       Phosphotyrosine; by autocatalysis.
FT                                {ECO:0000305|PubMed:3166375}.
FT   MOD_RES    1361   1361       Phosphotyrosine; by autocatalysis.
FT                                {ECO:0000305|PubMed:3166375}.
FT   CARBOHYD     43     43       N-linked (GlcNAc...).
FT                                {ECO:0000269|PubMed:16894147,
FT                                ECO:0000269|PubMed:23302862,
FT                                ECO:0000269|PubMed:2983222}.
FT   CARBOHYD     52     52       N-linked (GlcNAc...).
FT                                {ECO:0000269|PubMed:16894147,
FT                                ECO:0000269|PubMed:23302862}.
FT   CARBOHYD    105    105       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    138    138       N-linked (GlcNAc...).
FT                                {ECO:0000269|PubMed:16894147,
FT                                ECO:0000269|PubMed:23302862}.
FT   CARBOHYD    242    242       N-linked (GlcNAc...).
FT                                {ECO:0000269|PubMed:16894147,
FT                                ECO:0000269|PubMed:19159218,
FT                                ECO:0000269|PubMed:23302862}.
FT   CARBOHYD    282    282       N-linked (GlcNAc...).
FT                                {ECO:0000269|PubMed:16894147,
FT                                ECO:0000269|PubMed:23302862}.
FT   CARBOHYD    322    322       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    364    364       N-linked (GlcNAc...).
FT                                {ECO:0000269|PubMed:16894147}.
FT   CARBOHYD    424    424       N-linked (GlcNAc...).
FT                                {ECO:0000269|PubMed:16894147}.
FT   CARBOHYD    445    445       N-linked (GlcNAc...).
FT                                {ECO:0000269|PubMed:16894147,
FT                                ECO:0000269|PubMed:19349973}.
FT   CARBOHYD    541    541       N-linked (GlcNAc...).
FT                                {ECO:0000269|PubMed:1472036,
FT                                ECO:0000269|PubMed:19159218}.
FT   CARBOHYD    633    633       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    651    651       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    698    698       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    769    769       N-linked (GlcNAc...).
FT                                {ECO:0000269|PubMed:2983222}.
FT   CARBOHYD    782    782       N-linked (GlcNAc...). {ECO:0000255}.
FT   CARBOHYD    920    920       N-linked (GlcNAc...).
FT                                {ECO:0000269|PubMed:19349973}.
FT   CARBOHYD    933    933       N-linked (GlcNAc...). {ECO:0000255}.
FT   DISULFID     35     53
FT   DISULFID    153    182
FT   DISULFID    186    209
FT   DISULFID    196    215
FT   DISULFID    219    228
FT   DISULFID    223    234
FT   DISULFID    235    243
FT   DISULFID    239    252
FT   DISULFID    255    264
FT   DISULFID    268    280
FT   DISULFID    286    311
FT   DISULFID    293    301
FT   DISULFID    315    328
FT   DISULFID    331    335
FT   DISULFID    339    360
FT   DISULFID    462    495       {ECO:0000269|PubMed:1472036}.
FT   DISULFID    551    551       Interchain. {ECO:0000269|PubMed:1472036}.
FT   DISULFID    674    899
FT   DISULFID    825    834
FT   VAR_SEQ     745    756       Missing (in isoform Short).
FT                                {ECO:0000303|PubMed:15489334,
FT                                ECO:0000303|PubMed:2983222,
FT                                ECO:0000303|Ref.13}.
FT                                /FTId=VSP_002898.
FT   VARIANT       2      2       A -> G (in dbSNP:rs7508518).
FT                                {ECO:0000269|PubMed:15489334,
FT                                ECO:0000269|PubMed:2210055,
FT                                ECO:0000269|PubMed:2280779,
FT                                ECO:0000269|PubMed:2777789,
FT                                ECO:0000269|PubMed:2806055,
FT                                ECO:0000269|PubMed:2859121,
FT                                ECO:0000269|PubMed:2983222,
FT                                ECO:0000269|PubMed:3680248}.
FT                                /FTId=VAR_058395.
FT   VARIANT      42     42       N -> K (in RMS; impairs transport to the
FT                                plasma membrane and reduces the affinity
FT                                to bind insulin).
FT                                {ECO:0000269|PubMed:2365819}.
FT                                /FTId=VAR_004079.
FT   VARIANT      55     55       V -> A (in LEPRCH; Verona-1).
FT                                {ECO:0000269|PubMed:1607067}.
FT                                /FTId=VAR_004080.
FT   VARIANT      58     58       G -> R (in LEPRCH; Helmond; inhibits
FT                                processing and transport;
FT                                dbSNP:rs52836744).
FT                                {ECO:0000269|PubMed:1730625}.
FT                                /FTId=VAR_004081.
FT   VARIANT      86     86       D -> G (in IRAN type A).
FT                                {ECO:0000269|PubMed:9175790}.
FT                                /FTId=VAR_015907.
FT   VARIANT      89     89       L -> P (in IRAN type A).
FT                                {ECO:0000269|PubMed:9175790}.
FT                                /FTId=VAR_015908.
FT   VARIANT     113    113       R -> P (in LEPRCH; Atlanta-1; abolishes
FT                                insulin binding).
FT                                {ECO:0000269|PubMed:8419945}.
FT                                /FTId=VAR_004082.
FT   VARIANT     119    119       A -> V (in LEPRCH; markedly impairs
FT                                insulin binding).
FT                                /FTId=VAR_015909.
FT   VARIANT     120    120       L -> Q (in LEPRCH; inhibits receptor
FT                                processing).
FT                                {ECO:0000269|PubMed:12970295}.
FT                                /FTId=VAR_031518.
FT   VARIANT     146    146       I -> M (in LEPRCH; mild).
FT                                {ECO:0000269|PubMed:7815442,
FT                                ECO:0000269|PubMed:8326490}.
FT                                /FTId=VAR_015539.
FT   VARIANT     167    167       V -> L (in IRAN type A).
FT                                {ECO:0000269|PubMed:10733238}.
FT                                /FTId=VAR_015910.
FT   VARIANT     171    171       Y -> H (in dbSNP:rs1051692).
FT                                {ECO:0000269|PubMed:2859121}.
FT                                /FTId=VAR_058396.
FT   VARIANT     220    220       P -> L (in Ins resistance; severe).
FT                                {ECO:0000269|PubMed:8242067}.
FT                                /FTId=VAR_004083.
FT   VARIANT     228    228       C -> R (in a gastric adenocarcinoma
FT                                sample; somatic mutation).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041429.
FT   VARIANT     236    236       H -> R (in LEPRCH; Winnipeg; in one
FT                                patient with in RMS heterozygous compound
FT                                with S-386; may impair receptor
FT                                processing).
FT                                {ECO:0000269|PubMed:17201797,
FT                                ECO:0000269|PubMed:2365819}.
FT                                /FTId=VAR_004084.
FT   VARIANT     260    260       L -> P (in LEPRCH; Geldeimalsen).
FT                                {ECO:0000269|PubMed:2479553}.
FT                                /FTId=VAR_004085.
FT   VARIANT     279    279       R -> C (in IRAN type A; inhibits receptor
FT                                internalization).
FT                                {ECO:0000269|PubMed:12107746}.
FT                                /FTId=VAR_015540.
FT   VARIANT     279    279       R -> H (in IRAN type A; interferes with
FT                                receptor processing).
FT                                {ECO:0000269|PubMed:12970295}.
FT                                /FTId=VAR_031519.
FT   VARIANT     280    280       C -> Y (in IRAN type A).
FT                                {ECO:0000269|PubMed:11260230}.
FT                                /FTId=VAR_015911.
FT   VARIANT     301    301       C -> Y (in LEPRCH).
FT                                {ECO:0000269|PubMed:9703342}.
FT                                /FTId=VAR_015912.
FT   VARIANT     308    308       Missing (in LEPRCH; abolishes insulin
FT                                binding). {ECO:0000269|PubMed:7538143,
FT                                ECO:0000269|PubMed:8636294}.
FT                                /FTId=VAR_015913.
FT   VARIANT     350    350       S -> L (in RMS and LEPRCH).
FT                                {ECO:0000269|PubMed:12970295,
FT                                ECO:0000269|PubMed:8314008}.
FT                                /FTId=VAR_015914.
FT   VARIANT     362    362       Missing (in LEPRCH).
FT                                {ECO:0000269|PubMed:12538626}.
FT                                /FTId=VAR_015541.
FT   VARIANT     386    386       G -> S (in RMS; may impair receptor
FT                                processing).
FT                                {ECO:0000269|PubMed:17201797}.
FT                                /FTId=VAR_031520.
FT   VARIANT     393    393       G -> R (in LEPRCH; Verona-1).
FT                                {ECO:0000269|PubMed:1607067}.
FT                                /FTId=VAR_004086.
FT   VARIANT     409    409       F -> V (in IRAN type A).
FT                                {ECO:0000269|PubMed:8388389}.
FT                                /FTId=VAR_004087.
FT   VARIANT     439    439       W -> S (in LEPRCH; impairs transport of
FT                                the receptor to the cell surface).
FT                                {ECO:0000269|PubMed:8188715}.
FT                                /FTId=VAR_015542.
FT   VARIANT     448    448       I -> T (in dbSNP:rs1051691).
FT                                {ECO:0000269|PubMed:2859121}.
FT                                /FTId=VAR_015915.
FT   VARIANT     458    458       N -> D (in LEPRCH; partially inhibits
FT                                receptor processing and
FT                                autophosphorylation; strongly impairs ERK
FT                                phosphorylation; induces wild-type levels
FT                                of IRS-1 phosphorylation).
FT                                {ECO:0000269|PubMed:12970295}.
FT                                /FTId=VAR_031521.
FT   VARIANT     487    487       K -> E (in LEPRCH; ARK-1;
FT                                dbSNP:rs28933083).
FT                                {ECO:0000269|PubMed:2834824}.
FT                                /FTId=VAR_004088.
FT   VARIANT     489    489       N -> S (in IRAN type A;
FT                                dbSNP:rs28933085).
FT                                {ECO:0000269|PubMed:2365819}.
FT                                /FTId=VAR_004089.
FT   VARIANT     492    492       Q -> K (in dbSNP:rs1131851).
FT                                {ECO:0000269|PubMed:2859121}.
FT                                /FTId=VAR_015916.
FT   VARIANT     695    695       Q -> R (in dbSNP:rs55906835).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041430.
FT   VARIANT     762    762       R -> S (in IRAN type A).
FT                                {ECO:0000269|PubMed:3283938}.
FT                                /FTId=VAR_004090.
FT   VARIANT     811    811       G -> S (in dbSNP:rs35045353).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041431.
FT   VARIANT     830    830       P -> L (in dbSNP:rs2162771).
FT                                /FTId=VAR_055986.
FT   VARIANT     858    858       T -> A (in NIDDM; dbSNP:rs182552223).
FT                                {ECO:0000269|PubMed:7657032}.
FT                                /FTId=VAR_015917.
FT   VARIANT     925    925       I -> T (in LEPRCH; abolishes insulin
FT                                binding).
FT                                /FTId=VAR_015918.
FT   VARIANT     926    926       R -> W (in LEPRCH; markedly impairs
FT                                insulin binding).
FT                                /FTId=VAR_015919.
FT   VARIANT     937    937       T -> M (in LEPRCH; impaired receptor
FT                                processing).
FT                                /FTId=VAR_015920.
FT   VARIANT     997    997       P -> T (in RMS; reduces insulin binding).
FT                                {ECO:0000269|PubMed:12023989}.
FT                                /FTId=VAR_015921.
FT   VARIANT    1012   1012       V -> M (rare polymorphism;
FT                                dbSNP:rs1799816).
FT                                {ECO:0000269|PubMed:17344846,
FT                                ECO:0000269|PubMed:8314008,
FT                                ECO:0000269|PubMed:8432414,
FT                                ECO:0000269|PubMed:8458533,
FT                                ECO:0000269|PubMed:9199575}.
FT                                /FTId=VAR_004091.
FT   VARIANT    1020   1020       R -> Q (in IRAN type A).
FT                                {ECO:0000269|PubMed:2002058}.
FT                                /FTId=VAR_004092.
FT   VARIANT    1023   1023       I -> F. {ECO:0000269|PubMed:8890729}.
FT                                /FTId=VAR_015922.
FT   VARIANT    1035   1035       G -> V (in IRAN type A).
FT                                {ECO:0000269|PubMed:2544998}.
FT                                /FTId=VAR_004093.
FT   VARIANT    1055   1055       A -> V (in IRAN type A).
FT                                {ECO:0000269|PubMed:10733238}.
FT                                /FTId=VAR_015923.
FT   VARIANT    1065   1065       L -> V (in dbSNP:rs56395521).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041432.
FT   VARIANT    1075   1075       A -> D (in IRAN type A).
FT                                {ECO:0000269|PubMed:8243830}.
FT                                /FTId=VAR_004094.
FT   VARIANT    1095   1095       K -> E (in a NIDDM subject).
FT                                {ECO:0000269|PubMed:2040394}.
FT                                /FTId=VAR_015924.
FT   VARIANT    1119   1119       R -> W (in LEPRCH).
FT                                {ECO:0000269|PubMed:12970295,
FT                                ECO:0000269|PubMed:9249867}.
FT                                /FTId=VAR_015925.
FT   VARIANT    1143   1143       I -> T (in RMS; reduces insulin binding).
FT                                {ECO:0000269|PubMed:10443650,
FT                                ECO:0000269|PubMed:12023989}.
FT                                /FTId=VAR_015926.
FT   VARIANT    1158   1158       R -> Q (in NIDDM).
FT                                {ECO:0000269|PubMed:1470163}.
FT                                /FTId=VAR_015927.
FT   VARIANT    1158   1158       R -> W (in RMS; abolishes insulin
FT                                binding). {ECO:0000269|PubMed:10443650,
FT                                ECO:0000269|PubMed:12023989}.
FT                                /FTId=VAR_015928.
FT   VARIANT    1161   1161       A -> T (in IRAN type A;
FT                                dbSNP:rs28933084).
FT                                {ECO:0000269|PubMed:2168397}.
FT                                /FTId=VAR_004095.
FT   VARIANT    1162   1162       A -> E (in IRAN type A; impairs
FT                                proteolytic processing).
FT                                /FTId=VAR_004096.
FT   VARIANT    1180   1180       M -> I (in a patient with insulin
FT                                resistance).
FT                                {ECO:0000269|PubMed:1890161}.
FT                                /FTId=VAR_004097.
FT   VARIANT    1191   1191       R -> Q (in NIDDM).
FT                                {ECO:0000269|PubMed:1607076}.
FT                                /FTId=VAR_004098.
FT   VARIANT    1201   1201       R -> Q (in HHF5 and IRAN type A;
FT                                interferes with kinase activation by
FT                                insulin; dbSNP:rs28933086).
FT                                {ECO:0000269|PubMed:15161766,
FT                                ECO:0000269|PubMed:8288049}.
FT                                /FTId=VAR_015929.
FT   VARIANT    1201   1201       R -> W (in LEPRCH and RMS; reduces
FT                                insulin binding possibly due to reduced
FT                                receptor levels on the cell surface).
FT                                {ECO:0000269|PubMed:12023989,
FT                                ECO:0000269|PubMed:9703342}.
FT                                /FTId=VAR_015930.
FT   VARIANT    1205   1205       P -> L (in IRAN type A; moderate).
FT                                {ECO:0000269|PubMed:1563582,
FT                                ECO:0000269|PubMed:8314008}.
FT                                /FTId=VAR_004099.
FT   VARIANT    1206   1206       E -> D (in IRAN type A; accelerates
FT                                degradation of the protein and impairs
FT                                kinase activity).
FT                                /FTId=VAR_015931.
FT   VARIANT    1206   1206       E -> K (in LEPRCH).
FT                                {ECO:0000269|PubMed:9249867}.
FT                                /FTId=VAR_015932.
FT   VARIANT    1220   1220       W -> L (in IRAN type A; accelerates
FT                                degradation of the protein and impairs
FT                                kinase activity; dbSNP:rs52800171).
FT                                {ECO:0000269|PubMed:8390949}.
FT                                /FTId=VAR_004100.
FT   VARIANT    1227   1227       W -> S (in IRAN type A).
FT                                {ECO:0000269|PubMed:1963473}.
FT                                /FTId=VAR_004101.
FT   VARIANT    1282   1282       T -> A (in dbSNP:rs55875349).
FT                                {ECO:0000269|PubMed:17344846}.
FT                                /FTId=VAR_041433.
FT   VARIANT    1361   1361       Y -> C (in dbSNP:rs13306449).
FT                                {ECO:0000269|PubMed:7657032}.
FT                                /FTId=VAR_015933.
FT   VARIANT    1378   1378       R -> Q (in IRAN type A;
FT                                dbSNP:rs52826008).
FT                                {ECO:0000269|PubMed:8314008}.
FT                                /FTId=VAR_015934.
FT   MUTAGEN     991    991       L->A: Reduces interaction with IRS1 but
FT                                has no effect on interaction with SHC1.
FT                                {ECO:0000269|PubMed:7559478}.
FT   MUTAGEN     992    992       Y->A: Reduces interaction with IRS1 but
FT                                has no effect on interaction with SHC1.
FT                                {ECO:0000269|PubMed:7559478}.
FT   MUTAGEN     996    997       NP->AA: Abolishes interaction with IRS1.
FT                                Severely disrupts, but does not abolish
FT                                interaction with SHC1.
FT                                {ECO:0000269|PubMed:7559478}.
FT   MUTAGEN     996    996       N->A: Abolishes interaction with IRS1 and
FT                                significantly reduces interaction with
FT                                SHC1. Has no effect on interaction with
FT                                PIK3R1. {ECO:0000269|PubMed:7537849,
FT                                ECO:0000269|PubMed:7559478}.
FT   MUTAGEN     997    997       P->A: Abolishes interaction with IRS1 and
FT                                significantly reduces interaction with
FT                                SHC1. Has no effect on interaction with
FT                                PIK3R1. {ECO:0000269|PubMed:7537849,
FT                                ECO:0000269|PubMed:7559478}.
FT   MUTAGEN     998    998       E->A: Does not affect interaction with
FT                                IRS1, SHC1 or PIK3R1.
FT                                {ECO:0000269|PubMed:7537849}.
FT   MUTAGEN     999    999       Y->E: Abolishes interaction with IRS1 and
FT                                SHC1. {ECO:0000269|PubMed:2842060,
FT                                ECO:0000269|PubMed:7537849,
FT                                ECO:0000269|PubMed:7559478,
FT                                ECO:0000269|PubMed:9428692}.
FT   MUTAGEN     999    999       Y->F: Has no effect on insulin-stimulated
FT                                autophosphorylation, but inhibits the
FT                                biological activity of the receptor.
FT                                Abolishes interaction with IRS1 and
FT                                almost completely prevents interaction
FT                                with SHC1. Has no effect on interaction
FT                                with PIK3R1. Abolishes interaction with
FT                                STAT5B. {ECO:0000269|PubMed:2842060,
FT                                ECO:0000269|PubMed:7537849,
FT                                ECO:0000269|PubMed:7559478,
FT                                ECO:0000269|PubMed:9428692}.
FT   MUTAGEN    1000   1000       L->A,R: Severely reduces interaction with
FT                                SHC1. Has no effect on interaction with
FT                                IRS1. {ECO:0000269|PubMed:7559478}.
FT   MUTAGEN    1002   1002       A->D: Reduces interaction with IRS1 but
FT                                has no effect on interaction with SHC1.
FT                                {ECO:0000269|PubMed:7559478}.
FT   MUTAGEN    1011   1011       Y->A: Increases kinase activity.
FT                                {ECO:0000269|PubMed:12707268}.
FT   MUTAGEN    1057   1057       K->A: Abolishes the kinase activity and
FT                                abolishes interaction with IRS1, SHC1,
FT                                GRB7 and PIK3R1.
FT                                {ECO:0000269|PubMed:10803466,
FT                                ECO:0000269|PubMed:3101064,
FT                                ECO:0000269|PubMed:7537849}.
FT   MUTAGEN    1057   1057       K->M,R: Abolishes the kinase activity.
FT                                {ECO:0000269|PubMed:10803466,
FT                                ECO:0000269|PubMed:3101064,
FT                                ECO:0000269|PubMed:7537849}.
FT   MUTAGEN    1159   1159       D->N: Loss of kinase activity.
FT                                {ECO:0000269|PubMed:11598120}.
FT   MUTAGEN    1163   1163       R->Q: Loss of kinase activity.
FT                                {ECO:0000269|PubMed:11598120}.
FT   MUTAGEN    1189   1189       Y->F: Reduced interaction with GRB7.
FT                                {ECO:0000269|PubMed:10803466}.
FT   MUTAGEN    1190   1190       Y->F: Strongly reduced interaction with
FT                                GRB7. {ECO:0000269|PubMed:10803466}.
FT   CONFLICT    601    601       D -> N (in Ref. 19; AA sequence).
FT                                {ECO:0000305}.
FT   CONFLICT    830    830       P -> E (in Ref. 19; AA sequence).
FT                                {ECO:0000305}.
FT   CONFLICT   1278   1278       K -> N (in Ref. 2; CAA26096).
FT                                {ECO:0000305}.
FT   STRAND       33     42       {ECO:0000244|PDB:2HR7}.
FT   HELIX        45     50       {ECO:0000244|PDB:2HR7}.
FT   STRAND       53     65       {ECO:0000244|PDB:2HR7}.
FT   HELIX        70     72       {ECO:0000244|PDB:2HR7}.
FT   TURN         73     75       {ECO:0000244|PDB:2HR7}.
FT   STRAND       83     86       {ECO:0000244|PDB:2HR7}.
FT   STRAND       88     93       {ECO:0000244|PDB:2HR7}.
FT   TURN        100    102       {ECO:0000244|PDB:2HR7}.
FT   STRAND      118    124       {ECO:0000244|PDB:2HR7}.
FT   STRAND      141    149       {ECO:0000244|PDB:2HR7}.
FT   HELIX       160    162       {ECO:0000244|PDB:2HR7}.
FT   STRAND      171    175       {ECO:0000244|PDB:2HR7}.
FT   HELIX       176    178       {ECO:0000244|PDB:2HR7}.
FT   TURN        187    192       {ECO:0000244|PDB:2HR7}.
FT   STRAND      199    201       {ECO:0000244|PDB:2HR7}.
FT   STRAND      204    206       {ECO:0000244|PDB:2HR7}.
FT   STRAND      209    211       {ECO:0000244|PDB:2HR7}.
FT   HELIX       221    223       {ECO:0000244|PDB:2HR7}.
FT   STRAND      243    247       {ECO:0000244|PDB:2HR7}.
FT   STRAND      251    260       {ECO:0000244|PDB:2HR7}.
FT   STRAND      263    267       {ECO:0000244|PDB:2HR7}.
FT   STRAND      273    275       {ECO:0000244|PDB:2HR7}.
FT   TURN        276    278       {ECO:0000244|PDB:2HR7}.
FT   STRAND      279    281       {ECO:0000244|PDB:2HR7}.
FT   HELIX       283    295       {ECO:0000244|PDB:2HR7}.
FT   STRAND      298    300       {ECO:0000244|PDB:2HR7}.
FT   STRAND      305    307       {ECO:0000244|PDB:2HR7}.
FT   STRAND      310    314       {ECO:0000244|PDB:2HR7}.
FT   STRAND      319    321       {ECO:0000244|PDB:2HR7}.
FT   STRAND      327    330       {ECO:0000244|PDB:2HR7}.
FT   STRAND      332    334       {ECO:0000244|PDB:2HR7}.
FT   STRAND      338    348       {ECO:0000244|PDB:2HR7}.
FT   HELIX       351    355       {ECO:0000244|PDB:2HR7}.
FT   TURN        356    359       {ECO:0000244|PDB:2HR7}.
FT   STRAND      361    369       {ECO:0000244|PDB:2HR7}.
FT   HELIX       377    385       {ECO:0000244|PDB:2HR7}.
FT   STRAND      390    393       {ECO:0000244|PDB:2HR7}.
FT   STRAND      395    399       {ECO:0000244|PDB:2HR7}.
FT   STRAND      404    406       {ECO:0000244|PDB:2HR7}.
FT   TURN        422    424       {ECO:0000244|PDB:2HR7}.
FT   STRAND      425    430       {ECO:0000244|PDB:2HR7}.
FT   TURN        441    443       {ECO:0000244|PDB:2HR7}.
FT   STRAND      452    458       {ECO:0000244|PDB:2HR7}.
FT   HELIX       463    472       {ECO:0000244|PDB:2HR7}.
FT   TURN        476    478       {ECO:0000244|PDB:2HR7}.
FT   TURN        481    483       {ECO:0000244|PDB:2HR7}.
FT   STRAND      486    490       {ECO:0000244|PDB:2HR7}.
FT   HELIX       733    740       {ECO:0000244|PDB:4OGA}.
FT   HELIX       941    946       {ECO:0000244|PDB:2MFR}.
FT   HELIX       953    979       {ECO:0000244|PDB:2MFR}.
FT   HELIX      1009   1011       {ECO:0000244|PDB:1IR3}.
FT   HELIX      1014   1016       {ECO:0000244|PDB:1IRK}.
FT   HELIX      1020   1022       {ECO:0000244|PDB:3BU3}.
FT   STRAND     1023   1031       {ECO:0000244|PDB:3BU3}.
FT   STRAND     1033   1043       {ECO:0000244|PDB:3BU3}.
FT   STRAND     1046   1048       {ECO:0000244|PDB:2Z8C}.
FT   STRAND     1050   1057       {ECO:0000244|PDB:3BU3}.
FT   HELIX      1065   1078       {ECO:0000244|PDB:3BU3}.
FT   STRAND     1089   1093       {ECO:0000244|PDB:3BU3}.
FT   STRAND     1095   1098       {ECO:0000244|PDB:3BU3}.
FT   STRAND     1100   1104       {ECO:0000244|PDB:3BU3}.
FT   HELIX      1111   1117       {ECO:0000244|PDB:3BU3}.
FT   STRAND     1119   1121       {ECO:0000244|PDB:3ETA}.
FT   HELIX      1133   1152       {ECO:0000244|PDB:3BU3}.
FT   STRAND     1154   1156       {ECO:0000244|PDB:2AUH}.
FT   HELIX      1162   1164       {ECO:0000244|PDB:3BU3}.
FT   STRAND     1165   1167       {ECO:0000244|PDB:3BU3}.
FT   STRAND     1173   1175       {ECO:0000244|PDB:3BU3}.
FT   STRAND     1181   1183       {ECO:0000244|PDB:1IRK}.
FT   TURN       1185   1187       {ECO:0000244|PDB:3BU3}.
FT   STRAND     1190   1192       {ECO:0000244|PDB:4IBM}.
FT   STRAND     1194   1198       {ECO:0000244|PDB:3BU3}.
FT   HELIX      1200   1202       {ECO:0000244|PDB:3BU3}.
FT   HELIX      1205   1210       {ECO:0000244|PDB:3BU3}.
FT   HELIX      1215   1230       {ECO:0000244|PDB:3BU3}.
FT   TURN       1236   1239       {ECO:0000244|PDB:3BU3}.
FT   HELIX      1242   1250       {ECO:0000244|PDB:3BU3}.
FT   HELIX      1263   1272       {ECO:0000244|PDB:3BU3}.
FT   HELIX      1277   1279       {ECO:0000244|PDB:3BU3}.
FT   HELIX      1283   1290       {ECO:0000244|PDB:3BU3}.
FT   HELIX      1291   1293       {ECO:0000244|PDB:4IBM}.
FT   HELIX      1298   1301       {ECO:0000244|PDB:3BU3}.
FT   TURN       1303   1305       {ECO:0000244|PDB:2AUH}.
FT   HELIX      1307   1309       {ECO:0000244|PDB:1I44}.
SQ   SEQUENCE   1382 AA;  156333 MW;  709A955660739066 CRC64;
     MATGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL
     QILLMFKTRP EDFRDLSFPK LIMITDYLLL FRVYGLESLK DLFPNLTVIR GSRLFFNYAL
     VIFEMVHLKE LGLYNLMNIT RGSVRIEKNN ELCYLATIDW SRILDSVEDN YIVLNKDDNE
     ECGDICPGTA KGKTNCPATV INGQFVERCW THSHCQKVCP TICKSHGCTA EGLCCHSECL
     GNCSQPDDPT KCVACRNFYL DGRCVETCPP PYYHFQDWRC VNFSFCQDLH HKCKNSRRQG
     CHQYVIHNNK CIPECPSGYT MNSSNLLCTP CLGPCPKVCH LLEGEKTIDS VTSAQELRGC
     TVINGSLIIN IRGGNNLAAE LEANLGLIEE ISGYLKIRRS YALVSLSFFR KLRLIRGETL
     EIGNYSFYAL DNQNLRQLWD WSKHNLTITQ GKLFFHYNPK LCLSEIHKME EVSGTKGRQE
     RNDIALKTNG DQASCENELL KFSYIRTSFD KILLRWEPYW PPDFRDLLGF MLFYKEAPYQ
     NVTEFDGQDA CGSNSWTVVD IDPPLRSNDP KSQNHPGWLM RGLKPWTQYA IFVKTLVTFS
     DERRTYGAKS DIIYVQTDAT NPSVPLDPIS VSNSSSQIIL KWKPPSDPNG NITHYLVFWE
     RQAEDSELFE LDYCLKGLKL PSRTWSPPFE SEDSQKHNQS EYEDSAGECC SCPKTDSQIL
     KELEESSFRK TFEDYLHNVV FVPRKTSSGT GAEDPRPSRK RRSLGDVGNV TVAVPTVAAF
     PNTSSTSVPT SPEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAYV
     SARTMPEAKA DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYRR YGDEELHLCV
     SRKHFALERG CRLRGLSPGN YSVRIRATSL AGNGSWTEPT YFYVTDYLDV PSNIAKIIIG
     PLIFVFLFSV VIGSIYLFLR KRQPDGPLGP LYASSNPEYL SASDVFPCSV YVPDEWEVSR
     EKITLLRELG QGSFGMVYEG NARDIIKGEA ETRVAVKTVN ESASLRERIE FLNEASVMKG
     FTCHHVVRLL GVVSKGQPTL VVMELMAHGD LKSYLRSLRP EAENNPGRPP PTLQEMIQMA
     AEIADGMAYL NAKKFVHRDL AARNCMVAHD FTVKIGDFGM TRDIYETDYY RKGGKGLLPV
     RWMAPESLKD GVFTTSSDMW SFGVVLWEIT SLAEQPYQGL SNEQVLKFVM DGGYLDQPDN
     CPERVTDLMR MCWQFNPKMR PTFLEIVNLL KDDLHPSFPE VSFFHSEENK APESEELEME
     FEDMENVPLD RSSHCQREEA GGRDGGSSLG FKRSYEEHIP YTHMNGGKKN GRILTLPRSN
     PS
//


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