UniProt functional annotation for O15105



	UniProt functional annotation for O15105

UniProt code: O15105.

Organism: Homo sapiens (Human).

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

Function: Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access. Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1, which promotes its dephosphorylation. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. {ECO:0000269|PubMed:11163210, ECO:0000269|PubMed:12023024, ECO:0000269|PubMed:14718519, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:9892009}.

Subunit: Interacts with WWP1 (By similarity). Interacts with COPS5. Interacts with NEDD4L. Interacts with STAMBP. Interacts with RNF111, AXIN1 and AXIN2. Interacts with PPP1R15A. Interacts (via MH2 domain) with EP300. Interacts with ACVR1B, SMURF1, SMURF2 and TGFBR1; SMAD7 recruits SMURF1 and SMURF2 to the TGF-beta receptor and regulates its degradation. Interacts with PDPK1 (via PH domain). {ECO:0000250, ECO:0000269|PubMed:11163210, ECO:0000269|PubMed:11278251, ECO:0000269|PubMed:11483516, ECO:0000269|PubMed:12023024, ECO:0000269|PubMed:12408818, ECO:0000269|PubMed:14657019, ECO:0000269|PubMed:14718519, ECO:0000269|PubMed:14993265, ECO:0000269|PubMed:16061177, ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:16641086, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:9892009}.

Subcellular location: Nucleus {ECO:0000269|PubMed:14657019, ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:17327236}. Cytoplasm {ECO:0000269|PubMed:14657019, ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:17327236}. Note=Interaction with NEDD4L or RNF111 induces translocation from the nucleus to the cytoplasm (PubMed:16601693). TGF-beta stimulates its translocation from the nucleus to the cytoplasm. PDPK1 inhibits its translocation from the nucleus to the cytoplasm in response to TGF-beta (PubMed:17327236). {ECO:0000269|PubMed:16601693, ECO:0000269|PubMed:17327236}.

Tissue specificity: Ubiquitous with higher expression in the lung and vascular endothelium.

Induction: By TGFB1.

Ptm: Phosphorylation on Ser-249 does not affect its stability, nuclear localization or inhibitory function in TGFB signaling; however it affects its ability to regulate transcription (By similarity). Phosphorylated by PDPK1. {ECO:0000250|UniProtKB:O35253, ECO:0000269|PubMed:17327236}.

Ptm: Ubiquitinated by WWP1 (By similarity). Polyubiquitinated by RNF111, which is enhanced by AXIN1 and promotes proteasomal degradation (PubMed:14657019, PubMed:16601693). In response to TGF-beta, ubiquitinated by SMURF1; which promotes its degradation (PubMed:11278251). {ECO:0000250|UniProtKB:O35253, ECO:0000269|PubMed:11278251, ECO:0000269|PubMed:14657019, ECO:0000269|PubMed:16601693}.

Ptm: Acetylation prevents ubiquitination and degradation mediated by SMURF1. {ECO:0000269|PubMed:12408818}.

Disease: Colorectal cancer 3 (CRCS3) [MIM:612229]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:17934461}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity: Belongs to the dwarfin/SMAD 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:		Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access. Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1, which promotes its dephosphorylation. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. {ECO:0000269\|PubMed:11163210, ECO:0000269\|PubMed:12023024, ECO:0000269\|PubMed:14718519, ECO:0000269\|PubMed:17327236, ECO:0000269\|PubMed:9892009}.


Subunit:		Interacts with WWP1 (By similarity). Interacts with COPS5. Interacts with NEDD4L. Interacts with STAMBP. Interacts with RNF111, AXIN1 and AXIN2. Interacts with PPP1R15A. Interacts (via MH2 domain) with EP300. Interacts with ACVR1B, SMURF1, SMURF2 and TGFBR1; SMAD7 recruits SMURF1 and SMURF2 to the TGF-beta receptor and regulates its degradation. Interacts with PDPK1 (via PH domain). {ECO:0000250, ECO:0000269\|PubMed:11163210, ECO:0000269\|PubMed:11278251, ECO:0000269\|PubMed:11483516, ECO:0000269\|PubMed:12023024, ECO:0000269\|PubMed:12408818, ECO:0000269\|PubMed:14657019, ECO:0000269\|PubMed:14718519, ECO:0000269\|PubMed:14993265, ECO:0000269\|PubMed:16061177, ECO:0000269\|PubMed:16601693, ECO:0000269\|PubMed:16641086, ECO:0000269\|PubMed:17327236, ECO:0000269\|PubMed:9892009}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:14657019, ECO:0000269\|PubMed:16601693, ECO:0000269\|PubMed:17327236}. Cytoplasm {ECO:0000269\|PubMed:14657019, ECO:0000269\|PubMed:16601693, ECO:0000269\|PubMed:17327236}. Note=Interaction with NEDD4L or RNF111 induces translocation from the nucleus to the cytoplasm (PubMed:16601693). TGF-beta stimulates its translocation from the nucleus to the cytoplasm. PDPK1 inhibits its translocation from the nucleus to the cytoplasm in response to TGF-beta (PubMed:17327236). {ECO:0000269\|PubMed:16601693, ECO:0000269\|PubMed:17327236}.
Tissue specificity:		Ubiquitous with higher expression in the lung and vascular endothelium.
Induction:		By TGFB1.
Ptm:		Phosphorylation on Ser-249 does not affect its stability, nuclear localization or inhibitory function in TGFB signaling; however it affects its ability to regulate transcription (By similarity). Phosphorylated by PDPK1. {ECO:0000250\|UniProtKB:O35253, ECO:0000269\|PubMed:17327236}.
Ptm:		Ubiquitinated by WWP1 (By similarity). Polyubiquitinated by RNF111, which is enhanced by AXIN1 and promotes proteasomal degradation (PubMed:14657019, PubMed:16601693). In response to TGF-beta, ubiquitinated by SMURF1; which promotes its degradation (PubMed:11278251). {ECO:0000250\|UniProtKB:O35253, ECO:0000269\|PubMed:11278251, ECO:0000269\|PubMed:14657019, ECO:0000269\|PubMed:16601693}.
Ptm:		Acetylation prevents ubiquitination and degradation mediated by SMURF1. {ECO:0000269\|PubMed:12408818}.
Disease:		Colorectal cancer 3 (CRCS3) [MIM:612229]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269\|PubMed:17934461}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Similarity:		Belongs to the dwarfin/SMAD family. {ECO:0000305}.