SMAD4
This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasng blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome. [provided by RefSeq, Aug 2017]
Function
In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity).
Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling (PubMed:25514493).
Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.
Biological Process
Biological Process activin receptor signaling pathway1 PublicationIC:ComplexPortal
Biological Process adrenal gland developmentIEA:Ensembl
Biological Process agingIEA:Ensembl
Biological Process anatomical structure morphogenesisManual Assertion Based On ExperimentIBA:GO_Central
Biological Process atrioventricular canal developmentISS:BHF-UCL
Biological Process atrioventricular valve formationISS:BHF-UCL
Biological Process axon guidanceIEA:Ensembl
Biological Process BMP signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process brainstem developmentIEA:Ensembl
Biological Process branching involved in ureteric bud morphogenesisIEA:Ensembl
Biological Process cardiac conduction system development1 PublicationNAS:BHF-UCL
Biological Process cell differentiationManual Assertion Based On ExperimentIBA:GO_Central
Biological Process cell population proliferationIEA:Ensembl
Biological Process cellular iron ion homeostasisISS:BHF-UCL
Biological Process cellular response to BMP stimulus1 PublicationNAS:BHF-UCL
Biological Process cellular response to glucose stimulusIEA:Ensembl
Biological Process developmental growthIEA:Ensembl
Biological Process DNA-templated transcriptionManual Assertion Based On ExperimentIDA:ComplexPortal
Biological Process embryonic digit morphogenesisIEA:Ensembl
Biological Process endocardial cell differentiationISS:BHF-UCL
Biological Process endothelial cell activationIEA:Ensembl
Biological Process epithelial to mesenchymal transition involved in endocardial cushion formationIEA:Ensembl
Biological Process ERK1 and ERK2 cascadeIEA:Ensembl
Biological Process female gonad morphogenesisIEA:Ensembl
Biological Process formation of anatomical boundaryIEA:Ensembl
Biological Process gastrulation with mouth forming secondIEA:Ensembl
Biological Process in utero embryonic developmentIEA:Ensembl
Biological Process interleukin-6-mediated signaling pathwayISS:BHF-UCL
Biological Process intracellular signal transductionManual Assertion Based On ExperimentIMP:CACAO
Biological Process left ventricular cardiac muscle tissue morphogenesisISS:BHF-UCL
Biological Process mesendoderm developmentIEA:Ensembl
Biological Process metanephric mesenchyme morphogenesisIEA:Ensembl
Biological Process negative regulation of cardiac muscle hypertrophyISS:BHF-UCL
Biological Process negative regulation of cardiac myofibril assemblyISS:BHF-UCL
Biological Process negative regulation of cell deathIEA:Ensembl
Biological Process negative regulation of cell growthManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process negative regulation of cell population proliferationIEA:Ensembl
Biological Process negative regulation of DNA-templated transcriptionManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process negative regulation of ERK1 and ERK2 cascadeISS:BHF-UCL
Biological Process negative regulation of protein catabolic processIEA:Ensembl
Biological Process negative regulation of transcription by RNA polymerase IIISS:BHF-UCL
Biological Process nephrogenic mesenchyme morphogenesisIEA:Ensembl
Biological Process neural crest cell differentiationIEA:Ensembl
Biological Process neuron fate commitmentIEA:Ensembl
Biological Process osteoblast differentiationIEA:Ensembl
Biological Process outflow tract septum morphogenesisISS:BHF-UCL
Biological Process ovarian follicle developmentIEA:Ensembl
Biological Process positive regulation of BMP signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process positive regulation of cardiac muscle cell apoptotic processIEA:Ensembl
Biological Process positive regulation of cell proliferation involved in heart valve morphogenesisISS:BHF-UCL
Biological Process positive regulation of DNA-templated transcriptionManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of epithelial to mesenchymal transitionISS:BHF-UCL
Biological Process positive regulation of follicle-stimulating hormone secretionIEA:Ensembl
Biological Process positive regulation of histone H3-K4 methylationISS:BHF-UCL
Biological Process positive regulation of histone H3-K9 acetylationISS:BHF-UCL
Biological Process positive regulation of luteinizing hormone secretionIEA:Ensembl
Biological Process positive regulation of miRNA transcriptionIEA:Ensembl
Biological Process positive regulation of pathway-restricted SMAD protein phosphorylationISS:BHF-UCL
Biological Process positive regulation of SMAD protein signal transductionISS:BHF-UCL
Biological Process positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:GO_Central
Biological Process positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulusManual Assertion Based On ExperimentTAS:BHF-UCL
Biological Process positive regulation of transforming growth factor beta receptor signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process regulation of bindingIEA:Ensembl
Biological Process regulation of hair follicle developmentIEA:Ensembl
Biological Process regulation of transforming growth factor beta receptor signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process regulation of transforming growth factor beta2 productionManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process response to hypoxiaManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process response to transforming growth factor betaManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process sebaceous gland developmentIEA:Ensembl
Biological Process secondary palate developmentISS:BHF-UCL
Biological Process seminiferous tubule developmentIEA:Ensembl
Biological Process single fertilizationIEA:Ensembl
Biological Process SMAD protein complex assemblyManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process SMAD protein signal transductionManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process somite rostral/caudal axis specificationIEA:Ensembl
Biological Process spermatogenesisIEA:Ensembl
Biological Process transcription by RNA polymerase IIIEA:Ensembl
Biological Process transforming growth factor beta receptor signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process uterus developmentIEA:Ensembl
Biological Process ventricular septum morphogenesisISS:BHF-UCL
Biological Process wound healingIEA:Ensembl
Involvement in disease
Pancreatic cancer (PNCA):
A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.
Juvenile polyposis syndrome (JPS):
Autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers.
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT):
JP/HHT syndrome phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT) [MIM:187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or ACVRL1. All four genes encode proteins involved in the transforming-growth-factor-signaling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic etiology of this association is unknown.
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.
Myhre syndrome (MYHRS):
A syndrome characterized by pre- and postnatal growth deficiency, intellectual disability, generalized muscle hypertrophy and striking muscular build, decreased joint mobility, cryptorchidism, and unusual facies. Dysmorphic facial features include microcephaly, midface hypoplasia, prognathism, and blepharophimosis. Typical skeletal anomalies are short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur.
PTM
Phosphorylated by PDPK1.
Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiquitination by USP9X restores its competence to mediate TGF-beta signaling.
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