UniProt functional annotation for Q15796



	UniProt functional annotation for Q15796

UniProt code: Q15796.

Organism: Homo sapiens (Human).

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

Function: Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD2/SMAD4 complex, activates transcription. May act as a tumor suppressor in colorectal carcinoma. 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:16751101, ECO:0000269|PubMed:16862174, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:9892009}.

Subunit: Monomer; in the absence of TGF-beta (PubMed:9670020). Heterodimer; in the presence of TGF-beta (PubMed:9670020). Forms a heterodimer with co-SMAD, SMAD4, in the nucleus to form the transactivation complex SMAD2/SMAD4 (PubMed:9670020, PubMed:24324267, PubMed:15350224). Found in a complex with SMAD3 and TRIM33 upon addition of TGF-beta (PubMed:16751102). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts (via the MH2 domain) with ZFYVE9; may form trimers with the SMAD4 co-SMAD (PubMed:10615055). Interacts with TAZ/WWRT1 (PubMed:18568018). Interacts with FOXH1 (PubMed:9702198). Interacts with SNW1 (PubMed:11278756). Interacts with CREB-binding protein (CBP) and EP300 (PubMed:16862174). Interacts with SNON (PubMed:11389444). Interacts with ALK4/ACVR1B (PubMed:9892009, PubMed:10615055). Interacts with SKOR1 (PubMed:17292623). Interacts with SKOR2 (PubMed:16200078). Interacts with PRDM16 (PubMed:19049980). Interacts (via MH2 domain) with LEMD3 (PubMed:15601644, PubMed:15647271). Interacts with RBPMS (PubMed:17099224). Interacts with WWP1. Interacts (dephosphorylated form, via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling (PubMed:19289081). Interacts with PDPK1 (via PH domain) (PubMed:17327236). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation (PubMed:11387212). Interacts with USP15 (PubMed:21947082). Interacts with PPP5C (PubMed:22781750). Interacts with LDLRAD4 (via the SMAD interaction motif) (PubMed:24627487). Interacts (via MH2 domain) with PMEPA1 (via the SMAD interaction motif) (PubMed:20129061). Interacts with ZFHX3 (PubMed:25105025). Interacts with ZNF451 (PubMed:24324267). Interacts with SMURF2 when phosphorylated on Ser-465/467 (PubMed:11389444). Interacts with PPM1A (PubMed:16751101). Interacts with TGF-beta (PubMed:8980228). Interacts with TGFBR1 (PubMed:9865696). Interacts with TGIF (PubMed:10835638). Interacts with SMAD3 and TRIM33 (PubMed:16751102). Interacts with ZNF580 (PubMed:21599657). Interacts with NEDD4L in response to TGF-beta (By similarity). Interacts with HGS (By similarity). Interacts with AIP1 (By similarity). Interacts with WWP1 (By similarity). Interacts with PML (By similarity). Interacts weakly with ZNF8 (By similarity). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD2 inhibitors (By similarity). Interacts with YAP1 (when phosphorylated at 'Ser-127') (By similarity). {ECO:0000250|UniProtKB:Q62432, ECO:0000269|PubMed:10615055, ECO:0000269|PubMed:10835638, ECO:0000269|PubMed:11278756, ECO:0000269|PubMed:11387212, ECO:0000269|PubMed:11389444, ECO:0000269|PubMed:15350224, ECO:0000269|PubMed:15601644, ECO:0000269|PubMed:15647271, ECO:0000269|PubMed:16200078, ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:16751102, ECO:0000269|PubMed:16862174, ECO:0000269|PubMed:17099224, ECO:0000269|PubMed:17292623, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:18568018, ECO:0000269|PubMed:19049980, ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:20129061, ECO:0000269|PubMed:21599657, ECO:0000269|PubMed:21947082, ECO:0000269|PubMed:22781750, ECO:0000269|PubMed:24324267, ECO:0000269|PubMed:24627487, ECO:0000269|PubMed:25105025, ECO:0000269|PubMed:8980228, ECO:0000269|PubMed:9670020, ECO:0000269|PubMed:9702198, ECO:0000269|PubMed:9865696, ECO:0000269|PubMed:9892009}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:21145499, ECO:0000269|PubMed:9865696}. Nucleus {ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:21145499, ECO:0000269|PubMed:21599657, ECO:0000269|PubMed:22781750, ECO:0000269|PubMed:9865696}. Note=Cytoplasmic and nuclear in the absence of TGF-beta. On TGF-beta stimulation, migrates to the nucleus when complexed with SMAD4 (PubMed:9865696, PubMed:21145499). On dephosphorylation by phosphatase PPM1A, released from the SMAD2/SMAD4 complex, and exported out of the nucleus by interaction with RANBP1 (PubMed:16751101, PubMed:19289081). 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:Q62432, ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:21145499, ECO:0000269|PubMed:9865696}.

Tissue specificity: Expressed at high levels in skeletal muscle, endothelial cells, heart and placenta. {ECO:0000269|PubMed:21599657}.

Ptm: Phosphorylated on one or several of Thr-220, Ser-245, Ser-250, and Ser-255. In response to TGF-beta, phosphorylated on Ser-465/467 by TGF- beta and activin type 1 receptor kinases. TGF-beta-induced Ser-465/467 phosphorylation declines progressively in a KMT5A-dependent manner. Able to interact with SMURF2 when phosphorylated on Ser-465/467, recruiting other proteins, such as SNON, for degradation. In response to decorin, the naturally occurring inhibitor of TGF-beta signaling, phosphorylated on Ser-240 by CaMK2. Phosphorylated by MAPK3 upon EGF stimulation; which increases transcriptional activity and stability, and is blocked by calmodulin. Phosphorylated by PDPK1. {ECO:0000269|PubMed:11879191, ECO:0000269|PubMed:12193595, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:23478445, ECO:0000269|PubMed:8752209, ECO:0000269|PubMed:8980228, ECO:0000269|PubMed:9136927, ECO:0000269|PubMed:9346908}.

Ptm: In response to TGF-beta, ubiquitinated by NEDD4L; which promotes its degradation. Monoubiquitinated, leading to prevent DNA-binding (By similarity). Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (PubMed:21947082). Ubiquitinated by RNF111, leading to its degradation: only SMAD2 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD2 and regulating its turnover (By similarity). {ECO:0000250|UniProtKB:Q62432, ECO:0000269|PubMed:21947082}.

Ptm: Acetylated on Lys-19 by coactivators in response to TGF-beta signaling, which increases transcriptional activity. Isoform short: Acetylation increases DNA binding activity in vitro and enhances its association with target promoters in vivo. Acetylation in the nucleus by EP300 is enhanced by TGF-beta. {ECO:0000269|PubMed:16862174, ECO:0000269|PubMed:17074756, ECO:0000269|Ref.7}.

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:		Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD2/SMAD4 complex, activates transcription. May act as a tumor suppressor in colorectal carcinoma. 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:16751101, ECO:0000269\|PubMed:16862174, ECO:0000269\|PubMed:17327236, ECO:0000269\|PubMed:19289081, ECO:0000269\|PubMed:9892009}.


Subunit:		Monomer; in the absence of TGF-beta (PubMed:9670020). Heterodimer; in the presence of TGF-beta (PubMed:9670020). Forms a heterodimer with co-SMAD, SMAD4, in the nucleus to form the transactivation complex SMAD2/SMAD4 (PubMed:9670020, PubMed:24324267, PubMed:15350224). Found in a complex with SMAD3 and TRIM33 upon addition of TGF-beta (PubMed:16751102). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts (via the MH2 domain) with ZFYVE9; may form trimers with the SMAD4 co-SMAD (PubMed:10615055). Interacts with TAZ/WWRT1 (PubMed:18568018). Interacts with FOXH1 (PubMed:9702198). Interacts with SNW1 (PubMed:11278756). Interacts with CREB-binding protein (CBP) and EP300 (PubMed:16862174). Interacts with SNON (PubMed:11389444). Interacts with ALK4/ACVR1B (PubMed:9892009, PubMed:10615055). Interacts with SKOR1 (PubMed:17292623). Interacts with SKOR2 (PubMed:16200078). Interacts with PRDM16 (PubMed:19049980). Interacts (via MH2 domain) with LEMD3 (PubMed:15601644, PubMed:15647271). Interacts with RBPMS (PubMed:17099224). Interacts with WWP1. Interacts (dephosphorylated form, via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling (PubMed:19289081). Interacts with PDPK1 (via PH domain) (PubMed:17327236). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation (PubMed:11387212). Interacts with USP15 (PubMed:21947082). Interacts with PPP5C (PubMed:22781750). Interacts with LDLRAD4 (via the SMAD interaction motif) (PubMed:24627487). Interacts (via MH2 domain) with PMEPA1 (via the SMAD interaction motif) (PubMed:20129061). Interacts with ZFHX3 (PubMed:25105025). Interacts with ZNF451 (PubMed:24324267). Interacts with SMURF2 when phosphorylated on Ser-465/467 (PubMed:11389444). Interacts with PPM1A (PubMed:16751101). Interacts with TGF-beta (PubMed:8980228). Interacts with TGFBR1 (PubMed:9865696). Interacts with TGIF (PubMed:10835638). Interacts with SMAD3 and TRIM33 (PubMed:16751102). Interacts with ZNF580 (PubMed:21599657). Interacts with NEDD4L in response to TGF-beta (By similarity). Interacts with HGS (By similarity). Interacts with AIP1 (By similarity). Interacts with WWP1 (By similarity). Interacts with PML (By similarity). Interacts weakly with ZNF8 (By similarity). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD2 inhibitors (By similarity). Interacts with YAP1 (when phosphorylated at 'Ser-127') (By similarity). {ECO:0000250\|UniProtKB:Q62432, ECO:0000269\|PubMed:10615055, ECO:0000269\|PubMed:10835638, ECO:0000269\|PubMed:11278756, ECO:0000269\|PubMed:11387212, ECO:0000269\|PubMed:11389444, ECO:0000269\|PubMed:15350224, ECO:0000269\|PubMed:15601644, ECO:0000269\|PubMed:15647271, ECO:0000269\|PubMed:16200078, ECO:0000269\|PubMed:16751101, ECO:0000269\|PubMed:16751102, ECO:0000269\|PubMed:16862174, ECO:0000269\|PubMed:17099224, ECO:0000269\|PubMed:17292623, ECO:0000269\|PubMed:17327236, ECO:0000269\|PubMed:18568018, ECO:0000269\|PubMed:19049980, ECO:0000269\|PubMed:19289081, ECO:0000269\|PubMed:20129061, ECO:0000269\|PubMed:21599657, ECO:0000269\|PubMed:21947082, ECO:0000269\|PubMed:22781750, ECO:0000269\|PubMed:24324267, ECO:0000269\|PubMed:24627487, ECO:0000269\|PubMed:25105025, ECO:0000269\|PubMed:8980228, ECO:0000269\|PubMed:9670020, ECO:0000269\|PubMed:9702198, ECO:0000269\|PubMed:9865696, ECO:0000269\|PubMed:9892009}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:16751101, ECO:0000269\|PubMed:19289081, ECO:0000269\|PubMed:21145499, ECO:0000269\|PubMed:9865696}. Nucleus {ECO:0000269\|PubMed:16751101, ECO:0000269\|PubMed:19289081, ECO:0000269\|PubMed:21145499, ECO:0000269\|PubMed:21599657, ECO:0000269\|PubMed:22781750, ECO:0000269\|PubMed:9865696}. Note=Cytoplasmic and nuclear in the absence of TGF-beta. On TGF-beta stimulation, migrates to the nucleus when complexed with SMAD4 (PubMed:9865696, PubMed:21145499). On dephosphorylation by phosphatase PPM1A, released from the SMAD2/SMAD4 complex, and exported out of the nucleus by interaction with RANBP1 (PubMed:16751101, PubMed:19289081). 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:Q62432, ECO:0000269\|PubMed:16751101, ECO:0000269\|PubMed:19289081, ECO:0000269\|PubMed:21145499, ECO:0000269\|PubMed:9865696}.
Tissue specificity:		Expressed at high levels in skeletal muscle, endothelial cells, heart and placenta. {ECO:0000269\|PubMed:21599657}.
Ptm:		Phosphorylated on one or several of Thr-220, Ser-245, Ser-250, and Ser-255. In response to TGF-beta, phosphorylated on Ser-465/467 by TGF- beta and activin type 1 receptor kinases. TGF-beta-induced Ser-465/467 phosphorylation declines progressively in a KMT5A-dependent manner. Able to interact with SMURF2 when phosphorylated on Ser-465/467, recruiting other proteins, such as SNON, for degradation. In response to decorin, the naturally occurring inhibitor of TGF-beta signaling, phosphorylated on Ser-240 by CaMK2. Phosphorylated by MAPK3 upon EGF stimulation; which increases transcriptional activity and stability, and is blocked by calmodulin. Phosphorylated by PDPK1. {ECO:0000269\|PubMed:11879191, ECO:0000269\|PubMed:12193595, ECO:0000269\|PubMed:17327236, ECO:0000269\|PubMed:23478445, ECO:0000269\|PubMed:8752209, ECO:0000269\|PubMed:8980228, ECO:0000269\|PubMed:9136927, ECO:0000269\|PubMed:9346908}.
Ptm:		In response to TGF-beta, ubiquitinated by NEDD4L; which promotes its degradation. Monoubiquitinated, leading to prevent DNA-binding (By similarity). Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (PubMed:21947082). Ubiquitinated by RNF111, leading to its degradation: only SMAD2 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD2 and regulating its turnover (By similarity). {ECO:0000250\|UniProtKB:Q62432, ECO:0000269\|PubMed:21947082}.
Ptm:		Acetylated on Lys-19 by coactivators in response to TGF-beta signaling, which increases transcriptional activity. Isoform short: Acetylation increases DNA binding activity in vitro and enhances its association with target promoters in vivo. Acetylation in the nucleus by EP300 is enhanced by TGF-beta. {ECO:0000269\|PubMed:16862174, ECO:0000269\|PubMed:17074756, ECO:0000269\|Ref.7}.
Similarity:		Belongs to the dwarfin/SMAD family. {ECO:0000305}.