SMAD2

The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein mediates the signal of the transforming growth factor (TGF)-beta, and thus regulates multiple cellular processes, such as cell proliferation, apoptosis, and differentiation. This protein is recruited to the TGF-beta receptors through its interaction with the SMAD anchor for receptor activation (SARA) protein. In response to TGF-beta signal, this protein is phosphorylated by the TGF-beta receptors. The phosphorylation induces the dissociation of this protein with SARA and the association with the family member SMAD4. The association with SMAD4 is important for the translocation of this protein into the nucleus, where it binds to target promoters and forms a transcription repressor complex with other cofactors. This protein can also be phosphorylated by activin type 1 receptor kinase, and mediates the signal from the activin. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]

SMAD Family Member 2

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.

Activin receptor signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Adrenal gland developmentIEA:Ensembl
Anatomical structure morphogenesisManual Assertion Based On ExperimentIBA:GO_Central
Anterior/posterior pattern specificationISS:UniProtKB
BMP signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central
Cell differentiationManual Assertion Based On ExperimentIBA:GO_Central
Cell fate commitmentISS:UniProtKB
Common-partner SMAD protein phosphorylationManual Assertion Based On ExperimentIDA:MGI
Embryonic cranial skeleton morphogenesisIEA:Ensembl
Embryonic foregut morphogenesisIEA:Ensembl
Endoderm formationIEA:Ensembl
GastrulationManual Assertion Based On ExperimentTAS:BHF-UCL
In utero embryonic developmentIEA:Ensembl
Insulin secretionIEA:Ensembl
Intracellular signal transductionISS:UniProtKB
Lung developmentIEA:Ensembl
Mesoderm formationISS:UniProtKB
Negative regulation of cell population proliferationIEA:Ensembl
Negative regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIMP:BHF-UCL
Nodal signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Organ growthIEA:Ensembl
Pancreas developmentIEA:Ensembl
Paraxial mesoderm morphogenesisISS:UniProtKB
Pericardium developmentIEA:Ensembl
Positive regulation of BMP signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of epithelial to mesenchymal transitionISS:BHF-UCL
Positive regulation of gene expressionIEA:Ensembl
Positive regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetryManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:NTNU_SB
Positive regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:BHF-UCL
Post-embryonic developmentIEA:Ensembl
Primary miRNA processingManual Assertion Based On ExperimentTAS:BHF-UCL
Regulation of bindingISS:UniProtKB
Regulation of transforming growth factor beta receptor signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Response to cholesterolManual Assertion Based On ExperimentIDA:BHF-UCL
Response to glucoseIEA:Ensembl
Secondary palate developmentISS:BHF-UCL
Signal transduction involved in regulation of gene expressionIEA:Ensembl
SMAD protein complex assemblyManual Assertion Based On ExperimentIDA:BHF-UCL
SMAD protein signal transductionManual Assertion Based On ExperimentIBA:GO_Central
Transforming growth factor beta receptor signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Ureteric bud developmentIEA:Ensembl
Wound healingIEA:Ensembl
Zygotic specification of dorsal/ventral axisManual Assertion Based On ExperimentIMP:BHF-UCL

Cytoplasm
Nucleus
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).

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.
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).
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.