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 18-SEP-2013, entry version 194. 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; 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; 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; 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 AUTOPHOSPHORYLATION. 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; 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; 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; 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 MASS SPECTROMETRY. 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, AND MASS RP SPECTROMETRY. 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, AND MASS RP SPECTROMETRY. 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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/jc.80.5.1496; 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; 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; 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; 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; 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 -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a CC [protein]-L-tyrosine phosphate. 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 -!- 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 -!- 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. 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. 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. 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. 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. Note=The CC disease is caused by mutations affecting the gene represented in CC 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. Note=The disease is CC caused by 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. Note=The gene represented in CC this entry may be involved in disease 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. Note=The disease is caused by mutations CC affecting the gene represented in 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. Note=The disease is CC caused by mutations affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein CC kinase family. Insulin receptor subfamily. CC -!- SIMILARITY: Contains 3 fibronectin type-III domains. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Insulin receptor entry; CC URL="http://en.wikipedia.org/wiki/Insulin_receptor"; CC -!- WEB RESOURCE: Name=GeneReviews; CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/INSR"; CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution-NoDerivs License CC ----------------------------------------------------------------------- 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 IPI; IPI00025803; -. DR IPI; IPI00220325; -. DR PIR; A37348; INHUR. DR RefSeq; NP_000199.2; NM_000208.2. DR RefSeq; NP_001073285.1; NM_001079817.1. 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=1005-1298. 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=28-943. DR PDB; 2HR7; X-ray; 2.32 A; A/B=28-512. DR PDB; 2Z8C; X-ray; 3.25 A; A=1009-1310. 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=731-746. DR PDB; 3W12; X-ray; 4.30 A; E=28-337, F=731-746. DR PDB; 3W13; X-ray; 4.30 A; E=28-337, F=731-746. DR PDB; 3W14; X-ray; 4.40 A; E=28-620, F=731-746. 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; 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 ProteinModelPortal; P06213; -. DR SMR; P06213; 31-948, 1009-1339. DR DIP; DIP-480N; -. DR IntAct; P06213; 21. DR MINT; MINT-1516246; -. DR STRING; 9606.ENSP00000303830; -. DR PhosphoSite; P06213; -. DR DMDM; 308153655; -. DR PaxDb; P06213; -. DR PRIDE; P06213; -. DR DNASU; 3643; -. DR Ensembl; ENST00000302850; ENSP00000303830; ENSG00000171105. DR Ensembl; ENST00000341500; ENSP00000342838; ENSG00000171105. DR GeneID; 3643; -. DR KEGG; hsa:3643; -. DR UCSC; uc002mgd.1; human. 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 HOGENOM; HOG000038045; -. DR HOVERGEN; HBG006134; -. DR InParanoid; P06213; -. DR KO; K04527; -. DR OMA; DNCPERL; -. DR PhylomeDB; P06213; -. DR BRENDA; 2.7.10.1; 2681. DR Reactome; REACT_111102; Signal Transduction. DR SABIO-RK; P06213; -. DR SignaLink; P06213; -. DR BindingDB; P06213; -. DR ChEMBL; CHEMBL1981; -. DR ChiTaRS; INSR; human. DR DrugBank; DB00047; Insulin Glargine recombinant. DR DrugBank; DB00030; Insulin recombinant. DR DrugBank; DB00071; Insulin, porcine. DR EvolutionaryTrace; P06213; -. DR GeneWiki; Insulin_receptor; -. DR GenomeRNAi; 3643; -. DR NextBio; 14259; -. DR ArrayExpress; P06213; -. DR Bgee; P06213; -. DR CleanEx; HS_INSR; -. DR Genevestigator; P06213; -. DR GO; GO:0005901; C:caveola; IDA:BHF-UCL. DR GO; GO:0010008; C:endosome membrane; TAS:Reactome. DR GO; GO:0005899; C:insulin receptor complex; IMP:BHF-UCL. 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:0005009; F:insulin-activated receptor activity; IDA:UniProtKB. DR GO; GO:0005159; F:insulin-like growth factor receptor binding; IDA:BHF-UCL. 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: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:Compara. DR GO; GO:0031017; P:exocrine pancreas development; IEA:Compara. 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:0030238; P:male sex determination; IEA:Compara. 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 glycolysis; 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 cascade; IMP: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-dependent; IMP:BHF-UCL. 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; IPR000494; EGF_rcpt_L. DR InterPro; IPR003961; Fibronectin_type3. 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; 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; FN_III-like; 2. DR SUPFAM; SSF57184; Grow_fac_recept; 1. DR SUPFAM; SSF56112; Kinase_like; 1. DR PROSITE; PS50853; FN3; 3. 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 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 (Probable). FT TOPO_DOM 763 956 Extracellular (Probable). FT TRANSMEM 957 979 Helical; (Potential). FT TOPO_DOM 980 1382 Cytoplasmic (Probable). FT DOMAIN 622 695 Fibronectin type-III 1. FT DOMAIN 757 842 Fibronectin type-III 2. FT DOMAIN 850 946 Fibronectin type-III 3. FT DOMAIN 1023 1298 Protein kinase. FT NP_BIND 1104 1110 ATP. FT NP_BIND 1163 1164 ATP. 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 BINDING 1033 1033 ATP. FT BINDING 1057 1057 ATP. FT BINDING 1177 1177 ATP. FT SITE 66 66 Insulin-binding (Probable). FT MOD_RES 400 400 Phosphoserine. FT MOD_RES 401 401 Phosphotyrosine. FT MOD_RES 407 407 Phosphoserine. FT MOD_RES 992 992 Phosphotyrosine; by autocatalysis FT (Probable). FT MOD_RES 999 999 Phosphotyrosine; by autocatalysis. FT MOD_RES 1011 1011 Phosphotyrosine; by autocatalysis FT (Probable). FT MOD_RES 1185 1185 Phosphotyrosine; by autocatalysis. FT MOD_RES 1189 1189 Phosphotyrosine; by autocatalysis. FT MOD_RES 1190 1190 Phosphotyrosine; by autocatalysis. FT MOD_RES 1355 1355 Phosphotyrosine; by autocatalysis. FT MOD_RES 1361 1361 Phosphotyrosine; by autocatalysis. FT CARBOHYD 43 43 N-linked (GlcNAc...). FT CARBOHYD 52 52 N-linked (GlcNAc...). FT CARBOHYD 105 105 N-linked (GlcNAc...) (Potential). FT CARBOHYD 138 138 N-linked (GlcNAc...). FT CARBOHYD 242 242 N-linked (GlcNAc...). FT CARBOHYD 282 282 N-linked (GlcNAc...). FT CARBOHYD 322 322 N-linked (GlcNAc...) (Potential). FT CARBOHYD 364 364 N-linked (GlcNAc...). FT CARBOHYD 424 424 N-linked (GlcNAc...). FT CARBOHYD 445 445 N-linked (GlcNAc...). FT CARBOHYD 541 541 N-linked (GlcNAc...). FT CARBOHYD 633 633 N-linked (GlcNAc...) (Potential). FT CARBOHYD 651 651 N-linked (GlcNAc...) (Potential). FT CARBOHYD 698 698 N-linked (GlcNAc...) (Potential). FT CARBOHYD 769 769 N-linked (GlcNAc...). FT CARBOHYD 782 782 N-linked (GlcNAc...) (Potential). FT CARBOHYD 920 920 N-linked (GlcNAc...). FT CARBOHYD 933 933 N-linked (GlcNAc...) (Potential). 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 FT DISULFID 551 551 Interchain. FT DISULFID 674 899 FT DISULFID 825 834 FT VAR_SEQ 745 756 Missing (in isoform Short). FT /FTId=VSP_002898. FT VARIANT 2 2 A -> G (in dbSNP:rs7508518). 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 /FTId=VAR_004079. FT VARIANT 55 55 V -> A (in LEPRCH; Verona-1). FT /FTId=VAR_004080. FT VARIANT 58 58 G -> R (in LEPRCH; Helmond; inhibits FT processing and transport; FT dbSNP:rs52836744). FT /FTId=VAR_004081. FT VARIANT 86 86 D -> G (in IRAN type A). FT /FTId=VAR_015907. FT VARIANT 89 89 L -> P (in IRAN type A). FT /FTId=VAR_015908. FT VARIANT 113 113 R -> P (in LEPRCH; Atlanta-1; abolishes FT insulin binding). 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 /FTId=VAR_031518. FT VARIANT 146 146 I -> M (in LEPRCH; mild). FT /FTId=VAR_015539. FT VARIANT 167 167 V -> L (in IRAN type A). FT /FTId=VAR_015910. FT VARIANT 171 171 Y -> H (in dbSNP:rs1051692). FT /FTId=VAR_058396. FT VARIANT 220 220 P -> L (in Ins resistance; severe). FT /FTId=VAR_004083. FT VARIANT 228 228 C -> R (in a gastric adenocarcinoma FT sample; somatic mutation). 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 /FTId=VAR_004084. FT VARIANT 260 260 L -> P (in LEPRCH; Geldeimalsen). FT /FTId=VAR_004085. FT VARIANT 279 279 R -> C (in IRAN type A; inhibits receptor FT internalization). FT /FTId=VAR_015540. FT VARIANT 279 279 R -> H (in IRAN type A; interferes with FT receptor processing). FT /FTId=VAR_031519. FT VARIANT 280 280 C -> Y (in IRAN type A). FT /FTId=VAR_015911. FT VARIANT 301 301 C -> Y (in LEPRCH). FT /FTId=VAR_015912. FT VARIANT 308 308 Missing (in LEPRCH; abolishes insulin FT binding). FT /FTId=VAR_015913. FT VARIANT 350 350 S -> L (in RMS and LEPRCH). FT /FTId=VAR_015914. FT VARIANT 362 362 Missing (in LEPRCH). FT /FTId=VAR_015541. FT VARIANT 386 386 G -> S (in RMS; may impair receptor FT processing). FT /FTId=VAR_031520. FT VARIANT 393 393 G -> R (in LEPRCH; Verona-1). FT /FTId=VAR_004086. FT VARIANT 409 409 F -> V (in IRAN type A). FT /FTId=VAR_004087. FT VARIANT 439 439 W -> S (in LEPRCH; impairs transport of FT the receptor to the cell surface). FT /FTId=VAR_015542. FT VARIANT 448 448 I -> T (in dbSNP:rs1051691). 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 /FTId=VAR_031521. FT VARIANT 487 487 K -> E (in LEPRCH; ARK-1; FT dbSNP:rs28933083). FT /FTId=VAR_004088. FT VARIANT 489 489 N -> S (in IRAN type A; FT dbSNP:rs28933085). FT /FTId=VAR_004089. FT VARIANT 492 492 Q -> K (in dbSNP:rs1131851). FT /FTId=VAR_015916. FT VARIANT 695 695 Q -> R (in dbSNP:rs55906835). FT /FTId=VAR_041430. FT VARIANT 762 762 R -> S (in IRAN type A). FT /FTId=VAR_004090. FT VARIANT 811 811 G -> S (in dbSNP:rs35045353). 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 /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 /FTId=VAR_015921. FT VARIANT 1012 1012 V -> M (rare polymorphism; FT dbSNP:rs1799816). FT /FTId=VAR_004091. FT VARIANT 1020 1020 R -> Q (in IRAN type A). FT /FTId=VAR_004092. FT VARIANT 1023 1023 I -> F. FT /FTId=VAR_015922. FT VARIANT 1035 1035 G -> V (in IRAN type A). FT /FTId=VAR_004093. FT VARIANT 1055 1055 A -> V (in IRAN type A). FT /FTId=VAR_015923. FT VARIANT 1065 1065 L -> V (in dbSNP:rs56395521). FT /FTId=VAR_041432. FT VARIANT 1075 1075 A -> D (in IRAN type A). FT /FTId=VAR_004094. FT VARIANT 1095 1095 K -> E (in a NIDDM subject). FT /FTId=VAR_015924. FT VARIANT 1119 1119 R -> W (in LEPRCH). FT /FTId=VAR_015925. FT VARIANT 1143 1143 I -> T (in RMS; reduces insulin binding). FT /FTId=VAR_015926. FT VARIANT 1158 1158 R -> Q (in NIDDM). FT /FTId=VAR_015927. FT VARIANT 1158 1158 R -> W (in RMS; abolishes insulin FT binding). FT /FTId=VAR_015928. FT VARIANT 1161 1161 A -> T (in IRAN type A; FT dbSNP:rs28933084). 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 /FTId=VAR_004097. FT VARIANT 1191 1191 R -> Q (in NIDDM). 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 /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 /FTId=VAR_015930. FT VARIANT 1205 1205 P -> L (in IRAN type A; moderate). 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 /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 /FTId=VAR_004100. FT VARIANT 1227 1227 W -> S (in IRAN type A). FT /FTId=VAR_004101. FT VARIANT 1282 1282 T -> A (in dbSNP:rs55875349). FT /FTId=VAR_041433. FT VARIANT 1361 1361 Y -> C (in dbSNP:rs13306449). FT /FTId=VAR_015933. FT VARIANT 1378 1378 R -> Q (in IRAN type A; FT dbSNP:rs52826008). FT /FTId=VAR_015934. FT MUTAGEN 991 991 L->A: Reduces interaction with IRS1 but FT has no effect on interaction with SHC1. FT MUTAGEN 992 992 Y->A: Reduces interaction with IRS1 but FT has no effect on interaction with SHC1. FT MUTAGEN 996 997 NP->AA: Abolishes interaction with IRS1. FT Severely disrupts, but does not abolish FT interaction with SHC1. 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. 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. FT MUTAGEN 998 998 E->A: Does not affect interaction with FT IRS1, SHC1 or PIK3R1. FT MUTAGEN 999 999 Y->E: Abolishes interaction with IRS1 and FT SHC1. 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. FT MUTAGEN 1000 1000 L->A,R: Severely reduces interaction with FT SHC1. Has no effect on interaction with FT IRS1. FT MUTAGEN 1002 1002 A->D: Reduces interaction with IRS1 but FT has no effect on interaction with SHC1. FT MUTAGEN 1011 1011 Y->A: Increases kinase activity. FT MUTAGEN 1057 1057 K->A: Abolishes the kinase activity and FT abolishes interaction with IRS1, SHC1, FT GRB7 and PIK3R1. FT MUTAGEN 1057 1057 K->M,R: Abolishes the kinase activity. FT MUTAGEN 1159 1159 D->N: Loss of kinase activity. FT MUTAGEN 1163 1163 R->Q: Loss of kinase activity. FT MUTAGEN 1189 1189 Y->F: Reduced interaction with GRB7. FT MUTAGEN 1190 1190 Y->F: Strongly reduced interaction with FT GRB7. FT CONFLICT 601 601 D -> N (in Ref. 19; AA sequence). FT CONFLICT 830 830 P -> E (in Ref. 19; AA sequence). FT CONFLICT 1278 1278 K -> N (in Ref. 2; CAA26096). FT STRAND 33 42 FT HELIX 45 50 FT STRAND 53 65 FT HELIX 70 72 FT TURN 73 75 FT STRAND 83 86 FT STRAND 88 93 FT TURN 100 102 FT STRAND 118 124 FT STRAND 141 149 FT HELIX 160 162 FT STRAND 171 175 FT HELIX 176 178 FT TURN 187 192 FT STRAND 199 201 FT STRAND 204 206 FT STRAND 209 211 FT HELIX 221 223 FT STRAND 243 247 FT STRAND 251 260 FT STRAND 263 267 FT STRAND 273 275 FT TURN 276 278 FT STRAND 279 281 FT HELIX 283 295 FT STRAND 298 300 FT STRAND 305 307 FT STRAND 310 314 FT STRAND 319 321 FT STRAND 327 330 FT STRAND 332 334 FT STRAND 338 348 FT HELIX 351 355 FT TURN 356 359 FT STRAND 361 369 FT HELIX 377 385 FT STRAND 390 393 FT STRAND 395 399 FT STRAND 404 406 FT TURN 422 424 FT STRAND 425 430 FT TURN 441 443 FT STRAND 452 458 FT HELIX 463 472 FT TURN 476 478 FT TURN 481 483 FT STRAND 486 490 FT HELIX 1009 1011 FT HELIX 1014 1016 FT HELIX 1020 1022 FT STRAND 1023 1031 FT STRAND 1033 1043 FT STRAND 1046 1048 FT STRAND 1050 1057 FT HELIX 1065 1078 FT STRAND 1089 1093 FT STRAND 1095 1098 FT STRAND 1100 1104 FT HELIX 1111 1117 FT STRAND 1119 1121 FT HELIX 1133 1152 FT STRAND 1154 1156 FT HELIX 1162 1164 FT STRAND 1165 1167 FT STRAND 1173 1175 FT STRAND 1181 1183 FT TURN 1185 1187 FT HELIX 1188 1191 FT STRAND 1194 1198 FT HELIX 1200 1202 FT HELIX 1205 1210 FT HELIX 1215 1230 FT TURN 1236 1239 FT HELIX 1242 1250 FT HELIX 1263 1272 FT HELIX 1277 1279 FT HELIX 1283 1290 FT HELIX 1291 1293 FT HELIX 1298 1301 FT TURN 1303 1305 FT HELIX 1307 1309 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 //