SMAD3

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 functions as a transcriptional modulator activated by transforming growth factor-beta and is thought to play a role in the regulation of carcinogenesis. [provided by RefSeq, Apr 2009]

SMAD Family Member 3

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 SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.

Activation of cysteine-type endopeptidase activity involved in apoptotic processManual Assertion Based On ExperimentIMP:BHF-UCL
Activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathwayIEA:Ensembl
Activin receptor signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Adrenal gland developmentIEA:Ensembl
Anatomical structure morphogenesisManual Assertion Based On ExperimentIBA:GO_Central
BMP signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central
Cell differentiationManual Assertion Based On ExperimentIBA:GO_Central
Cell-cell junction organizationManual Assertion Based On ExperimentIMP:BHF-UCL
Cellular response to transforming growth factor beta stimulusManual Assertion Based On ExperimentIDA:CAFA
Cellular response to virusIEA:Ensembl
Developmental growthIEA:Ensembl
Embryonic cranial skeleton morphogenesisIEA:Ensembl
Embryonic foregut morphogenesisIEA:Ensembl
Embryonic pattern specificationIEA:Ensembl
Endoderm developmentIEA:Ensembl
Extrinsic apoptotic signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Heart loopingIEA:Ensembl
Immune responseManual Assertion Based On ExperimentIMP:BHF-UCL
Immune system developmentIEA:Ensembl
In utero embryonic developmentIEA:Ensembl
JNK cascadeIEA:Ensembl
Lens fiber cell differentiationIEA:Ensembl
Liver developmentIEA:Ensembl
Mesoderm formationIEA:Ensembl
Negative regulation of apoptotic processIEA:Ensembl
Negative regulation of cardiac muscle hypertrophy in response to stressIEA:Ensembl
Negative regulation of cell growthManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of cell population proliferationManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of cytosolic calcium ion concentrationManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of fat cell differentiationManual Assertion Based On ExperimentIDA:BHF-UCL
Negative regulation of inflammatory responseIEA:Ensembl
Negative regulation of lung blood pressureIEA:Ensembl
Negative regulation of osteoblast differentiationIEA:Ensembl
Negative regulation of osteoblast proliferationIEA:Ensembl
Negative regulation of protein catabolic processIEA:Ensembl
Negative regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:ARUK-UCL
Negative regulation of wound healingIEA:Ensembl
Nodal signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Osteoblast developmentIEA:Ensembl
Paraxial mesoderm morphogenesisIEA:Ensembl
Pericardium developmentIEA:Ensembl
Positive regulation of alkaline phosphatase activityIEA:Ensembl
Positive regulation of bone mineralizationIEA:Ensembl
Positive regulation of canonical Wnt signaling pathwayIEA:Ensembl
Positive regulation of cell migrationIEA:Ensembl
Positive regulation of chondrocyte differentiationIEA:Ensembl
Positive regulation of DNA-binding transcription factor activity1 PublicationNAS:BHF-UCL
Positive regulation of epithelial to mesenchymal transitionManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of extracellular matrix assemblyManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of focal adhesion assemblyIEA:Ensembl
Positive regulation of gene expressionManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of interleukin-1 beta productionIEA:Ensembl
Positive regulation of miRNA transcriptionManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of nitric oxide biosynthetic processManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of positive chemotaxisIEA:Ensembl
Positive regulation of protein import into nucleus1 PublicationNAS:BHF-UCL
Positive regulation of stress fiber assemblyIEA:Ensembl
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of transforming growth factor beta3 productionIEA:Ensembl
Primary miRNA processingManual Assertion Based On ExperimentTAS:BHF-UCL
Protein stabilizationIEA:Ensembl
Regulation of bindingIEA:Ensembl
Regulation of epithelial cell proliferationIEA:Ensembl
Regulation of immune responseIEA:Ensembl
Regulation of miRNA transcription1 PublicationIC:ARUK-UCL
Regulation of striated muscle tissue developmentIEA:Ensembl
Regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:NTNU_SB
Regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:ComplexPortal
Regulation of transforming growth factor beta receptor signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Regulation of transforming growth factor beta2 productionManual Assertion Based On ExperimentIMP:BHF-UCL
Response to hypoxiaManual Assertion Based On ExperimentIMP: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
SomitogenesisIEA:Ensembl
T cell activationIEA:Ensembl
Thyroid gland developmentIEA:Ensembl
TransdifferentiationIEA:Ensembl
Transforming growth factor beta receptor signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Ureteric bud developmentIEA:Ensembl
Wound healingManual Assertion Based On ExperimentTAS: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:15799969, PubMed:21145499).
Through the action of the phosphatase PPM1A, released from the SMAD2/SMAD4 complex, and exported out of the nucleus by interaction with RANBP1 (PubMed:16751101, PubMed:19289081).
Co-localizes with LEMD3 at the nucleus inner membrane (PubMed:15601644).
MAPK-mediated phosphorylation appears to have no effect on nuclear import (PubMed:19218245).
PDPK1 prevents its nuclear translocation in response to TGF-beta (PubMed:17327236).
Localized mainly to the nucleus in the early stages of embryo development with expression becoming evident in the cytoplasm of the inner cell mass at the blastocyst stage (By similarity).

Colorectal cancer (CRC):
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.
Loeys-Dietz syndrome 3 (LDS3):
An aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and mental retardation.

Phosphorylated on serine and threonine residues. Enhanced phosphorylation in the linker region on Thr-179, Ser-204 and Ser-208 on EGF and TGF-beta treatment. Ser-208 is the main site of MAPK-mediated phosphorylation. CDK-mediated phosphorylation occurs in a cell-cycle dependent manner and inhibits both the transcriptional activity and antiproliferative functions of SMAD3. This phosphorylation is inhibited by flavopiridol. Maximum phosphorylation at the G1/S junction. Also phosphorylated on serine residues in the C-terminal SXS motif by TGFBR1 and ACVR1. TGFBR1-mediated phosphorylation at these C-terminal sites is required for interaction with SMAD4, nuclear location and transactivational activity, and appears to be a prerequisite for the TGF-beta mediated phosphorylation in the linker region. Dephosphorylated in the C-terminal SXS motif by PPM1A. This dephosphorylation disrupts the interaction with SMAD4, promotes nuclear export and terminates TGF-beta-mediated signaling. Phosphorylation at Ser-418 by CSNK1G2/CK1 promotes ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses. Phosphorylated by PDPK1.
Acetylation in the nucleus by EP300 in the MH2 domain regulates positively its transcriptional activity and is enhanced by TGF-beta.
Poly-ADP-ribosylated by PARP1 and PARP2. ADP-ribosylation negatively regulates SMAD3 transcriptional responses during the course of TGF-beta signaling.
Ubiquitinated. Monoubiquitinated, leading to prevent DNA-binding (PubMed:21947082).
Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes (PubMed:21947082).
Ubiquitinated by RNF111, leading to its degradation: only SMAD3 proteins that are 'in use' are targeted by RNF111, RNF111 playing a key role in activating SMAD3 and regulating its turnover (By similarity).
Undergoes STUB1-mediated ubiquitination and degradation (PubMed:24613385).