UniProt functional annotation for P46937



	UniProt functional annotation for P46937

UniProt code: P46937.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Transcriptional regulator which can act both as a coactivator and a corepressor and is the critical downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis (PubMed:17974916, PubMed:18280240, PubMed:18579750, PubMed:21364637, PubMed:30447097). The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ (PubMed:18158288). Plays a key role in tissue tension and 3D tissue shape by regulating cortical actomyosin network formation. Acts via ARHGAP18, a Rho GTPase activating protein that suppresses F-actin polymerization (PubMed:25778702). Plays a key role in controlling cell proliferation in response to cell contact. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration (PubMed:18158288). The presence of TEAD transcription factors are required for it to stimulate gene expression, cell growth, anchorage- independent growth, and epithelial mesenchymal transition (EMT) induction (PubMed:18579750). Suppresses ciliogenesis via acting as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1 (PubMed:25849865). In conjunction with WWTR1, involved in the regulation of TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation (By similarity). {ECO:0000250|UniProtKB:P46938, ECO:0000269|PubMed:17974916, ECO:0000269|PubMed:18158288, ECO:0000269|PubMed:18280240, ECO:0000269|PubMed:18579750, ECO:0000269|PubMed:21364637, ECO:0000269|PubMed:25778702, ECO:0000269|PubMed:25849865, ECO:0000269|PubMed:30447097}.

Function: [Isoform 2]: Activates the C-terminal fragment (CTF) of ERBB4 (isoform 3). {ECO:0000269|PubMed:12807903}.

Function: [Isoform 3]: Activates the C-terminal fragment (CTF) of ERBB4 (isoform 3). {ECO:0000269|PubMed:12807903}.

Subunit: Binds to the SH3 domain of the YES kinase. Binds to WBP1 and WBP2 (PubMed:9202023). Binds, in vitro, through the WW1 domain, to neural isoforms of ENAH that contain the PPSY motif (By similarity). The phosphorylated form interacts with YWHAB (PubMed:17974916). Interacts (via WW domains) with LATS1 (via PPxY motif 2) (PubMed:18158288). Interacts with LATS2 (PubMed:18158288). Interacts with TEAD1, TEAD2, TEAD3 and TEAD4 (PubMed:18579750, PubMed:20123905, PubMed:20123908). Interacts with TP73 (PubMed:18280240). Interacts with RUNX1 (PubMed:18280240). Interacts with HCK (PubMed:17535448). Interacts (via WW domains) with PTPN14 (via PPxY motif 2); this interaction leads to the cytoplasmic sequestration of YAP1 and inhibits its transcriptional coactivator activity (PubMed:22525271). Interacts (when phosphorylated at Ser-127) with SMAD2, SMAD3 and WWTR1 (By similarity). Interacts with PRRG2 (via cytoplasmic domain) (PubMed:17502622). Interacts (via WW domains) with PRRG4 (via cytoplasmic domain) (PubMed:23873930). {ECO:0000250|UniProtKB:P46938, ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:17502622, ECO:0000269|PubMed:17535448, ECO:0000269|PubMed:17974916, ECO:0000269|PubMed:18158288, ECO:0000269|PubMed:18280240, ECO:0000269|PubMed:18579750, ECO:0000269|PubMed:20123905, ECO:0000269|PubMed:20123908, ECO:0000269|PubMed:22525271, ECO:0000269|PubMed:23873930, ECO:0000269|PubMed:9202023}.

Subunit: [Isoform 3]: Interacts (via WW domain 1) with isoform 3 of ERBB4 (via PPxY motif 2). {ECO:0000269|PubMed:12807903}.

Subunit: [Isoform 2]: Interacts (via WW domain 1) with isoform 3 of ERBB4 (via PPxY motif 2). {ECO:0000269|PubMed:12807903}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:18158288, ECO:0000269|PubMed:18280240, ECO:0000269|PubMed:20048001, ECO:0000269|PubMed:22525271, ECO:0000269|PubMed:25849865}. Nucleus {ECO:0000269|PubMed:17974916, ECO:0000269|PubMed:18158288, ECO:0000269|PubMed:18280240, ECO:0000269|PubMed:20048001, ECO:0000269|PubMed:21145499, ECO:0000269|PubMed:22525271, ECO:0000269|PubMed:25849865, ECO:0000269|PubMed:28169360, ECO:0000269|PubMed:30447097}. Note=Both phosphorylation and cell density can regulate its subcellular localization (PubMed:18158288, PubMed:20048001). Phosphorylation sequesters it in the cytoplasm by inhibiting its translocation into the nucleus (PubMed:18158288, PubMed:20048001). At low density, predominantly nuclear and is translocated to the cytoplasm at high density (PubMed:18158288, PubMed:20048001, PubMed:25849865). PTPN14 induces translocation from the nucleus to the cytoplasm (PubMed:22525271). Localized mainly to the nucleus in the early stages of embryo development with expression becoming evident in the cytoplasm at the blastocyst and epiblast stages (By similarity). {ECO:0000250|UniProtKB:P46938, ECO:0000269|PubMed:18158288, ECO:0000269|PubMed:20048001, ECO:0000269|PubMed:22525271, ECO:0000269|PubMed:25849865}.

Tissue specificity: Increased expression seen in some liver and prostate cancers. Isoforms lacking the transactivation domain found in striatal neurons of patients with Huntington disease (at protein level). {ECO:0000269|PubMed:16461361, ECO:0000269|PubMed:17974916, ECO:0000269|PubMed:7782338}.

Domain: The first coiled-coil region mediates most of the interaction with TEAD transcription factors. {ECO:0000269|PubMed:20123905}.

Ptm: Phosphorylated by LATS1 and LATS2; leading to cytoplasmic translocation and inactivation (PubMed:18158288, PubMed:20048001). Phosphorylated by ABL1; leading to YAP1 stabilization, enhanced interaction with TP73 and recruitment onto proapoptotic genes; in response to DNA damage (PubMed:18280240). Phosphorylation at Ser-400 and Ser-403 by CK1 is triggered by previous phosphorylation at Ser-397 by LATS proteins and leads to YAP1 ubiquitination by SCF(beta-TRCP) E3 ubiquitin ligase and subsequent degradation (PubMed:20048001). Phosphorylated at Thr-119, Ser-138, Thr-154, Ser-367 and Thr-412 by MAPK8/JNK1 and MAPK9/JNK2, which is required for the regulation of apoptosis by YAP1 (PubMed:21364637). {ECO:0000269|PubMed:18158288, ECO:0000269|PubMed:18280240, ECO:0000269|PubMed:20048001, ECO:0000269|PubMed:21364637}.

Ptm: Ubiquitinated by SCF(beta-TRCP) E3 ubiquitin ligase. {ECO:0000269|PubMed:20048001}.

Disease: Coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or mental retardation (COB1) [MIM:120433]: An autosomal dominant disease characterized by uveal colobomata, microphthalmia, cataract and cleft lip/palate. Considerable variability is observed among patients, uveal colobomata being the most constant feature. Some patients manifest mental retardation of varying degree and/or sensorineural, mid-frequency hearing loss. {ECO:0000269|PubMed:24462371}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: [Isoform 9]: Highest expression in ovary and placenta, lowest in skeletal muscle and brain. {ECO:0000305}.

Similarity: Belongs to the YAP1 family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Transcriptional regulator which can act both as a coactivator and a corepressor and is the critical downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis (PubMed:17974916, PubMed:18280240, PubMed:18579750, PubMed:21364637, PubMed:30447097). The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ (PubMed:18158288). Plays a key role in tissue tension and 3D tissue shape by regulating cortical actomyosin network formation. Acts via ARHGAP18, a Rho GTPase activating protein that suppresses F-actin polymerization (PubMed:25778702). Plays a key role in controlling cell proliferation in response to cell contact. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration (PubMed:18158288). The presence of TEAD transcription factors are required for it to stimulate gene expression, cell growth, anchorage- independent growth, and epithelial mesenchymal transition (EMT) induction (PubMed:18579750). Suppresses ciliogenesis via acting as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1 (PubMed:25849865). In conjunction with WWTR1, involved in the regulation of TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation (By similarity). {ECO:0000250\|UniProtKB:P46938, ECO:0000269\|PubMed:17974916, ECO:0000269\|PubMed:18158288, ECO:0000269\|PubMed:18280240, ECO:0000269\|PubMed:18579750, ECO:0000269\|PubMed:21364637, ECO:0000269\|PubMed:25778702, ECO:0000269\|PubMed:25849865, ECO:0000269\|PubMed:30447097}.



Function:		[Isoform 2]: Activates the C-terminal fragment (CTF) of ERBB4 (isoform 3). {ECO:0000269\|PubMed:12807903}.



Function:		[Isoform 3]: Activates the C-terminal fragment (CTF) of ERBB4 (isoform 3). {ECO:0000269\|PubMed:12807903}.


Subunit:		Binds to the SH3 domain of the YES kinase. Binds to WBP1 and WBP2 (PubMed:9202023). Binds, in vitro, through the WW1 domain, to neural isoforms of ENAH that contain the PPSY motif (By similarity). The phosphorylated form interacts with YWHAB (PubMed:17974916). Interacts (via WW domains) with LATS1 (via PPxY motif 2) (PubMed:18158288). Interacts with LATS2 (PubMed:18158288). Interacts with TEAD1, TEAD2, TEAD3 and TEAD4 (PubMed:18579750, PubMed:20123905, PubMed:20123908). Interacts with TP73 (PubMed:18280240). Interacts with RUNX1 (PubMed:18280240). Interacts with HCK (PubMed:17535448). Interacts (via WW domains) with PTPN14 (via PPxY motif 2); this interaction leads to the cytoplasmic sequestration of YAP1 and inhibits its transcriptional coactivator activity (PubMed:22525271). Interacts (when phosphorylated at Ser-127) with SMAD2, SMAD3 and WWTR1 (By similarity). Interacts with PRRG2 (via cytoplasmic domain) (PubMed:17502622). Interacts (via WW domains) with PRRG4 (via cytoplasmic domain) (PubMed:23873930). {ECO:0000250\|UniProtKB:P46938, ECO:0000269\|PubMed:12807903, ECO:0000269\|PubMed:17502622, ECO:0000269\|PubMed:17535448, ECO:0000269\|PubMed:17974916, ECO:0000269\|PubMed:18158288, ECO:0000269\|PubMed:18280240, ECO:0000269\|PubMed:18579750, ECO:0000269\|PubMed:20123905, ECO:0000269\|PubMed:20123908, ECO:0000269\|PubMed:22525271, ECO:0000269\|PubMed:23873930, ECO:0000269\|PubMed:9202023}.
Subunit:		[Isoform 3]: Interacts (via WW domain 1) with isoform 3 of ERBB4 (via PPxY motif 2). {ECO:0000269\|PubMed:12807903}.
Subunit:		[Isoform 2]: Interacts (via WW domain 1) with isoform 3 of ERBB4 (via PPxY motif 2). {ECO:0000269\|PubMed:12807903}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:18158288, ECO:0000269\|PubMed:18280240, ECO:0000269\|PubMed:20048001, ECO:0000269\|PubMed:22525271, ECO:0000269\|PubMed:25849865}. Nucleus {ECO:0000269\|PubMed:17974916, ECO:0000269\|PubMed:18158288, ECO:0000269\|PubMed:18280240, ECO:0000269\|PubMed:20048001, ECO:0000269\|PubMed:21145499, ECO:0000269\|PubMed:22525271, ECO:0000269\|PubMed:25849865, ECO:0000269\|PubMed:28169360, ECO:0000269\|PubMed:30447097}. Note=Both phosphorylation and cell density can regulate its subcellular localization (PubMed:18158288, PubMed:20048001). Phosphorylation sequesters it in the cytoplasm by inhibiting its translocation into the nucleus (PubMed:18158288, PubMed:20048001). At low density, predominantly nuclear and is translocated to the cytoplasm at high density (PubMed:18158288, PubMed:20048001, PubMed:25849865). PTPN14 induces translocation from the nucleus to the cytoplasm (PubMed:22525271). Localized mainly to the nucleus in the early stages of embryo development with expression becoming evident in the cytoplasm at the blastocyst and epiblast stages (By similarity). {ECO:0000250\|UniProtKB:P46938, ECO:0000269\|PubMed:18158288, ECO:0000269\|PubMed:20048001, ECO:0000269\|PubMed:22525271, ECO:0000269\|PubMed:25849865}.
Tissue specificity:		Increased expression seen in some liver and prostate cancers. Isoforms lacking the transactivation domain found in striatal neurons of patients with Huntington disease (at protein level). {ECO:0000269\|PubMed:16461361, ECO:0000269\|PubMed:17974916, ECO:0000269\|PubMed:7782338}.
Domain:		The first coiled-coil region mediates most of the interaction with TEAD transcription factors. {ECO:0000269\|PubMed:20123905}.
Ptm:		Phosphorylated by LATS1 and LATS2; leading to cytoplasmic translocation and inactivation (PubMed:18158288, PubMed:20048001). Phosphorylated by ABL1; leading to YAP1 stabilization, enhanced interaction with TP73 and recruitment onto proapoptotic genes; in response to DNA damage (PubMed:18280240). Phosphorylation at Ser-400 and Ser-403 by CK1 is triggered by previous phosphorylation at Ser-397 by LATS proteins and leads to YAP1 ubiquitination by SCF(beta-TRCP) E3 ubiquitin ligase and subsequent degradation (PubMed:20048001). Phosphorylated at Thr-119, Ser-138, Thr-154, Ser-367 and Thr-412 by MAPK8/JNK1 and MAPK9/JNK2, which is required for the regulation of apoptosis by YAP1 (PubMed:21364637). {ECO:0000269\|PubMed:18158288, ECO:0000269\|PubMed:18280240, ECO:0000269\|PubMed:20048001, ECO:0000269\|PubMed:21364637}.
Ptm:		Ubiquitinated by SCF(beta-TRCP) E3 ubiquitin ligase. {ECO:0000269\|PubMed:20048001}.
Disease:		Coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or mental retardation (COB1) [MIM:120433]: An autosomal dominant disease characterized by uveal colobomata, microphthalmia, cataract and cleft lip/palate. Considerable variability is observed among patients, uveal colobomata being the most constant feature. Some patients manifest mental retardation of varying degree and/or sensorineural, mid-frequency hearing loss. {ECO:0000269\|PubMed:24462371}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		[Isoform 9]: Highest expression in ovary and placenta, lowest in skeletal muscle and brain. {ECO:0000305}.
Similarity:		Belongs to the YAP1 family. {ECO:0000305}.