SMAD4
entrez
4089
canonical
uniprot
Q13485
canonical
ensembl
ENSG00000141646
resolver
ensp
ENSP00000341551
resolver
ensp
ENSP00000381452
resolver
ensp
ENSP00000464772
resolver
ensp
ENSP00000465874
resolver
ensp
ENSP00000465878
resolver
ensp
ENSP00000466934
resolver
ensp
ENSP00000641128
resolver
ensp
ENSP00000708984
resolver
enst
ENST00000342988
resolver
enst
ENST00000398417
resolver
enst
ENST00000588860
resolver
enst
ENST00000589076
resolver
enst
ENST00000589941
resolver
enst
ENST00000590061
resolver
enst
ENST00000971069
resolver
genesymbol
SMAD4
resolver
genesymbol_syn
DPC4
resolver
genesymbol_syn
MADH4
resolver
hgnc
HGNC:6770
resolver
uniprot
A0A024R274
resolver
uniprot
A8K405
resolver
uniprot_entry
A0A024R274_HUMAN
resolver
uniprot_entry
SMAD4_HUMAN
resolver
uniprot_sec
A8K405
resolver
amino_acid_sequence
MDNMSITNTPTSNDACLSIVHSLMCHRQGGESETFAKRAIESLVKKLKEKKDELDSLITAITTNGAHPSKCVTIQRTLDGRLQVAGRKGFPHVIYARLWRWPDLHKNELKHVKYCQYAFDLKCDSVCVNPYHYERVVSPGIDLSGLTLQSNAPSSMMVKDEYVHDFEGQPSLSTEGHSIQTIQHPPSNRASTETYSTPALLAPSESNATSTANFPNIPVASTSQPASILGGSHSEGLLQIASGPQPGQQQNGFTGQPATYHHNSTTTWTGSRTAPYTPNLPHHQNGHLQHHPPMPPHPGHYWPVHNELAFQPPISNHPAPEYWCSIAYFEMDVQVGETFKVPSSCPIVTVDGYVDPSGGDRFCLGQLSNVHRTEAIERARLHIGKGVQLECKGEGDVWVRCLSDHAVFVQSYYLDREAGRAPGDAVHKIYPSAYIKVFDLRQCHRQMQQQAATAQAAAAAQAAAVAGNIPGPGSVGGIAPAISLSAAAGIGVDDLRRLCILRMSFVKGWGPDYPRQSIKETPCWIEIHLHRALQLLDEVLHTMPIADPQPLD
uniprot
proteins
disease_involvement
DISEASE: Pancreatic cancer (PNCA) [MIM:260350]: 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. {ECO:0000269|PubMed:8553070}. Note=The gene represented in this entry may be involved in disease pathogenesis.; DISEASE: Juvenile polyposis syndrome (JPS) [MIM:174900]: 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. {ECO:0000269|PubMed:12417513, ECO:0000269|PubMed:9811934}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT) [MIM:175050]: 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. {ECO:0000269|PubMed:15031030}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Colorectal cancer (CRC) [MIM:114500]: 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:16959974}. Note=The disease may be caused by variants affecting the gene represented in this entry.; DISEASE: Note=SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs. {ECO:0000269|PubMed:21898662}.; DISEASE: Myhre syndrome (MYHRS) [MIM:139210]: An autosomal dominant 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. {ECO:0000269|PubMed:22158539, ECO:0000269|PubMed:22243968}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
function
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. {ECO:0000250, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:25514493, ECO:0000269|PubMed:9389648}.
uniprot
proteins
mass_dalton
60439
uniprot
proteins
mutagenesis
MUTAGEN 416; /note="R->S: No effect on heterotrimerization. Partially diminished transcriptional activation."; /evidence="ECO:0000269|PubMed:11224571"; MUTAGEN 496; /note="R->S: No effect on heterotrimerization. Partially diminished transcriptional activation."; MUTAGEN 502; /note="R->S: No effect on heterotrimerization. Greatly reduced transcriptional activation."; /evidence="ECO:0000269|PubMed:11224571"; MUTAGEN 515; /note="R->S: Reduced heterotrimerization."; /evidence="ECO:0000269|PubMed:11224571"; MUTAGEN 519; /note="K->R: Abolishes ubiquitination."; /evidence="ECO:0000269|PubMed:19135894
uniprot
proteins
post_translational_modification
PTM: Phosphorylated by PDPK1. {ECO:0000269|PubMed:17327236}.; PTM: 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. {ECO:0000269|PubMed:19135894}.
uniprot
proteins
protein_family
Dwarfin/SMAD family
uniprot
proteins
pubmed
10636916
uniprot
proteins
pubmed
10647180
uniprot
proteins
pubmed
10660046
uniprot
proteins
pubmed
11224571
uniprot
proteins
pubmed
11741830
uniprot
proteins
pubmed
11818334
uniprot
proteins
pubmed
12370310
uniprot
proteins
pubmed
12417513
uniprot
proteins
pubmed
12941698
uniprot
proteins
pubmed
14525983
uniprot
proteins
pubmed
14630787
uniprot
proteins
pubmed
14671321
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15031030
uniprot
proteins
pubmed
15350224
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15799969
uniprot
proteins
pubmed
15820681
uniprot
proteins
pubmed
15881652
uniprot
proteins
pubmed
16777850
uniprot
proteins
pubmed
16959974
uniprot
proteins
pubmed
17099224
uniprot
proteins
pubmed
17327236
uniprot
proteins
pubmed
18568018
uniprot
proteins
pubmed
19135894
uniprot
proteins
pubmed
19608861
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21898662
uniprot
proteins
pubmed
22158539
uniprot
proteins
pubmed
22243968
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
24324267
uniprot
proteins
pubmed
25218447
uniprot
proteins
pubmed
25310401
uniprot
proteins
pubmed
25514493
uniprot
proteins
pubmed
25755297
uniprot
proteins
pubmed
26878725
uniprot
proteins
pubmed
28112733
uniprot
proteins
pubmed
39143229
uniprot
proteins
pubmed
8553070
uniprot
proteins
pubmed
8774881
uniprot
proteins
pubmed
9098646
uniprot
proteins
pubmed
9214508
uniprot
proteins
pubmed
9389648
uniprot
proteins
pubmed
9670020
uniprot
proteins
pubmed
9707553
uniprot
proteins
pubmed
9811934
uniprot
proteins
sequence_length
552
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15799969, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:39143229}. Nucleus {ECO:0000269|PubMed:15799969}. Note=Cytoplasmic in the absence of ligand. Migrates to the nucleus when complexed with R-SMAD (PubMed:15799969). PDPK1 prevents its nuclear translocation in response to TGF-beta (PubMed:17327236). {ECO:0000269|PubMed:15799969, ECO:0000269|PubMed:17327236}.
uniprot
proteins