Description: Homo sapiens SMAD family member 4 (SMAD4), mRNA. RefSeq Summary (NM_005359): 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]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data because no single transcript was available for the full length of the gene. The extent of this transcript is supported by transcript alignments. Transcript (Including UTRs) Position: hg19 chr18:48,556,583-48,611,411 Size: 54,829 Total Exon Count: 12 Strand: + Coding Region Position: hg19 chr18:48,573,417-48,604,837 Size: 31,421 Coding Exon Count: 11
ID:SMAD4_HUMAN DESCRIPTION: RecName: Full=Mothers against decapentaplegic homolog 4; Short=MAD homolog 4; Short=Mothers against DPP homolog 4; AltName: Full=Deletion target in pancreatic carcinoma 4; AltName: Full=SMAD family member 4; Short=SMAD 4; Short=Smad4; Short=hSMAD4; FUNCTION: 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. 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 syngernistic 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. SUBUNIT: Interacts with CITED2 (By similarity). Monomer; in the absence of TGF-beta activation. Heterodimer; on TGF-beta activation. Composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Interacts with ZNF423; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with ZNF521; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for syngernistic transcriptional activity in response to TGF-beta. Interacts with CITED1. Interacts with PDPK1 (via PH domain) (By similarity). Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive. INTERACTION: Q9UI36:DACH1; NbExp=3; IntAct=EBI-347263, EBI-347111; Q92988:DLX4; NbExp=5; IntAct=EBI-347263, EBI-1752755; O43524:FOXO3; NbExp=4; IntAct=EBI-347263, EBI-1644164; P23769:GATA2; NbExp=2; IntAct=EBI-347263, EBI-2806671; Q9UBE8:NLK; NbExp=5; IntAct=EBI-347263, EBI-366978; P12755:SKI; NbExp=3; IntAct=EBI-347263, EBI-347281; Q15796:SMAD2; NbExp=12; IntAct=EBI-347263, EBI-1040141; P84022:SMAD3; NbExp=9; IntAct=EBI-347263, EBI-347161; P08047:SP1; NbExp=2; IntAct=EBI-347263, EBI-298336; Q9UPN9:TRIM33; NbExp=5; IntAct=EBI-347263, EBI-2214398; P63279:UBE2I; NbExp=3; IntAct=EBI-347263, EBI-80168; Q93008:USP9X; NbExp=2; IntAct=EBI-347263, EBI-302524; P70398:Usp9x (xeno); NbExp=4; IntAct=EBI-347263, EBI-2214043; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Cytoplasmic in the absence of ligand. Migrates to the nucleus when complexed with R- SMAD. PDPK1 prevents its nuclear translocation in response to TGF- beta. DOMAIN: The MH1 domain is required for DNA binding. DOMAIN: The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import. PTM: Phosphorylated by PDPK1. 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. Deubiqitination by USP9X restores its competence to mediate TGF-beta signaling. DISEASE: Defects in SMAD4 are a cause of pancreatic cancer (PNCA) [MIM:260350]. DISEASE: Defects in SMAD4 are a cause of juvenile polyposis syndrome (JPS) [MIM:174900]; also known as juvenile intestinal polyposis (JIP). JPS is an 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. DISEASE: Defects in SMAD4 are a cause of 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. DISEASE: Defects in SMAD4 may be a cause of colorectal cancer (CRC) [MIM:114500]. DISEASE: Defects in SMAD4 may be a cause of primary pulmonary hypertension (PPH1) [MIM:178600]. A rare 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 PPH1 is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs. DISEASE: Defects in SMAD4 are the cause of Myhre syndrome (MYHRS) [MIM:139210]. MYHRS is a syndrome characterized by pre- and postnatal growth deficiency, mental retardation, 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. SIMILARITY: Belongs to the dwarfin/SMAD family. SIMILARITY: Contains 1 MH1 (MAD homology 1) domain. SIMILARITY: Contains 1 MH2 (MAD homology 2) domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/SMAD4ID371.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SMAD4"; WEB RESOURCE: Name=Mendelian genes SMAD family member 4 (SMAD4); Note=Leiden Open Variation Database (LOVD); URL="http://www.lovd.nl/SMAD4";
Juvenile polyposis syndrome; polyposis, gastric Friedl, W. et al. 2002, Juvenile polyposis: massive gastric polyposis ismore common in MADH4 mutation carriers than in BMPR1A mutation carriers., Human genetics. 2002 Jul;111(1):108-11.
[PubMed 12136244]
A remarkable prevalence of massive gastric polyposis was observed in patients with MADH4 mutations when compared with patients with BMPR1A mutations or without identified mutations. This is the first genotype-phenotype correlation observed in JPS.
polyposis, juvenile Sayed, M. G. et al. 2002, Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis., Annals of surgical oncology. 2002 Nov;9(9):901-6.
[PubMed 12417513]
Patients with germline SMAD4 or BMPR1A mutations have a more prominent JP phenotype than those without, and SMAD4 mutations predispose to UGI polyposis.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q13485
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
AK303027 - Homo sapiens cDNA FLJ59261 complete cds, highly similar to Mothers against decapentaplegic homolog 4 (SMAD4). AK290770 - Homo sapiens cDNA FLJ76143 complete cds, highly similar to Homo sapiens SMAD, mothers against DPP homolog 4 (SMAD4), mRNA. BC002379 - Homo sapiens SMAD family member 4, mRNA (cDNA clone MGC:8602 IMAGE:2961238), complete cds. JD490888 - Sequence 471912 from Patent EP1572962. U44378 - Human homozygous deletion target in pancreatic carcinoma (DPC4) mRNA, complete cds. AB385155 - Synthetic construct DNA, clone: pF1KB5682, Homo sapiens SMAD4 gene for SMAD family member 4, complete cds, without stop codon, in Flexi system. KU178168 - Homo sapiens SMAD family member 4 isoform 1 (SMAD4) mRNA, partial cds. KU178169 - Homo sapiens SMAD family member 4 isoform 2 (SMAD4) mRNA, complete cds, alternatively spliced. KJ891568 - Synthetic construct Homo sapiens clone ccsbBroadEn_00962 SMAD4 gene, encodes complete protein. KR710003 - Synthetic construct Homo sapiens clone CCSBHm_00008876 SMAD4 (SMAD4) mRNA, encodes complete protein. KR710004 - Synthetic construct Homo sapiens clone CCSBHm_00008879 SMAD4 (SMAD4) mRNA, encodes complete protein. KR710005 - Synthetic construct Homo sapiens clone CCSBHm_00008890 SMAD4 (SMAD4) mRNA, encodes complete protein. KR710006 - Synthetic construct Homo sapiens clone CCSBHm_00008892 SMAD4 (SMAD4) mRNA, encodes complete protein. DQ891840 - Synthetic construct clone IMAGE:100004470; FLH180498.01X; RZPDo839C11134D SMAD, mothers against DPP homolog 4 (Drosophila) (SMAD4) gene, encodes complete protein. DQ895028 - Synthetic construct Homo sapiens clone IMAGE:100009488; FLH180494.01L; RZPDo839C11133D SMAD, mothers against DPP homolog 4 (Drosophila) (SMAD4) gene, encodes complete protein. BX647129 - Homo sapiens mRNA; cDNA DKFZp686A13166 (from clone DKFZp686A13166). LQ726439 - Sequence 17 from Patent WO2018094385. JD428618 - Sequence 409642 from Patent EP1572962. JD298947 - Sequence 279971 from Patent EP1572962. JD263355 - Sequence 244379 from Patent EP1572962. JD133375 - Sequence 114399 from Patent EP1572962. JD440064 - Sequence 421088 from Patent EP1572962. JD518823 - Sequence 499847 from Patent EP1572962. JD507450 - Sequence 488474 from Patent EP1572962. JD504802 - Sequence 485826 from Patent EP1572962. JD550163 - Sequence 531187 from Patent EP1572962. JD130961 - Sequence 111985 from Patent EP1572962. JD061352 - Sequence 42376 from Patent EP1572962. JD350864 - Sequence 331888 from Patent EP1572962. JD388562 - Sequence 369586 from Patent EP1572962. JD388563 - Sequence 369587 from Patent EP1572962. JD541331 - Sequence 522355 from Patent EP1572962. JD043992 - Sequence 25016 from Patent EP1572962. JD163470 - Sequence 144494 from Patent EP1572962. JD554470 - Sequence 535494 from Patent EP1572962. JD312190 - Sequence 293214 from Patent EP1572962. DQ572040 - Homo sapiens piRNA piR-40152, complete sequence. MP414203 - Sequence 17 from Patent WO2019222178. MC019443 - JP 2020500514-A/17: CHEMICAL COMPOSITIONS AND METHODS OF USING SAME.
Biochemical and Signaling Pathways
KEGG - Kyoto Encyclopedia of Genes and Genomes hsa04110 - Cell cycle hsa04310 - Wnt signaling pathway hsa04350 - TGF-beta signaling pathway hsa04520 - Adherens junction hsa05200 - Pathways in cancer hsa05210 - Colorectal cancer hsa05212 - Pancreatic cancer hsa05220 - Chronic myeloid leukemia
BioCarta from NCI Cancer Genome Anatomy Project h_ctcfPathway - CTCF: First Multivalent Nuclear Factor h_tgfbPathway - TGF beta signaling pathway h_tob1Pathway - Role of Tob in T-cell activation h_alkPathway - ALK in cardiac myocytes h_wntPathway - WNT Signaling Pathway h_g1Pathway - Cell Cycle: G1/S Check Point h_nthiPathway - NFkB activation by Nontypeable Hemophilus influenzae
Reactome (by CSHL, EBI, and GO)
Protein Q13485 (Reactome details) participates in the following event(s):
R-HSA-170847 Phosphorylated SMAD2 and SMAD3 form a complex with SMAD4 R-HSA-201422 Phospho-R-Smad1/5/8 forms a complex with Co-Smad R-HSA-870437 USP9X (FAM) deubiquitinates SMAD4 R-HSA-209055 PPM1A dephosphorylates nuclear SMAD2/3 R-HSA-2179276 SMURF2 monoubiquitinates SMAD3 R-HSA-173488 The SMAD2/3:SMAD4 complex transfers to the nucleus R-HSA-2031355 WWTR1 binds SMAD2/3:SMAD4 heterotrimer R-HSA-201472 The phospho-R-Smad1/5/8:Co-Smad transfers to the nucleus R-HSA-870479 USP9X (FAM) binds to ubiquitinated SMAD4 R-HSA-870477 Ubiquitinated SMAD4 translocates from the nucleus to the cytosol R-HSA-173481 SKI/SKIL binds SMAD complex, suppressing TGF-beta signaling R-HSA-870538 TRIM33 (Ectodermin) binds SMAD heterotrimer in the nucleus R-HSA-1225919 Phospho R-SMAD(SMAD2/3):CO-SMAD(SMAD4):FOXH1 binds Activin Response Element R-HSA-1535903 Phospho R-SMAD(SMAD2/3):CO-SMAD(SMAD4):FOXO3 binds FoxO3a-binding elements R-HSA-2127257 SMAD2/3:SMAD4 heterotrimer forms a complex with RBL1, E2F4/5 and DP1/2 R-HSA-2176475 Phosphorylation of SMAD2 and SMAD3 linker regions by CDK8 or CDK9 R-HSA-2186607 TGIF recruits HDAC1 to SMAD2/3:SMAD4 heterotrimer R-HSA-2186643 MEN1 binds SMAD2/3:SMAD4 heterotrimer R-HSA-2187309 SMAD2/3:SMAD4 heterotrimer binds SP1 R-HSA-2187330 PARP1 binds SMAD2/3:SMAD4 heterotrimer R-HSA-2187388 PPM1A protein phosphatase binds phosphorylated SMAD2/3 R-HSA-2186747 Ubiquitination of SKI/SKIL by RNF111/SMURF2 R-NUL-2186755 Ubiquitination of SKI/SKIL by Rnf111 R-HSA-201423 SKI complexes with the Smad complex, suppressing BMP2 signalling R-HSA-8877941 RUNX2 binds SMAD1 in the nucleus R-HSA-480204 POU5F1 (OCT4), SOX2, NANOG, KLF4, PBX1, SMAD2 bind the NANOG promoter R-HSA-1112609 POU5F1 (OCT4), SOX2, NANOG, ZSCAN10, PRDM14, SMAD2, FOXP1-ES bind the POU5F1 (OCT4) promoter R-HSA-870449 TRIM33 monoubiquitinates SMAD4 R-HSA-2176491 NEDD4L binds phosphorylated linker region of SMAD2/3 R-HSA-2179274 SMURF2 binds SMAD3 phosphorylated in the linker region R-HSA-8878143 RUNX3 binds SMAD3 and SMAD4 R-HSA-2187325 PARP1 ADP-ribosylates SMAD3 and SMAD4 R-HSA-2106579 WWTR1:SMAD translocates to the nucleus R-NUL-2186736 Rnf111 binds SKI/SKIL in complex with SMAD2/3:SMAD4 upon TGF-beta stimulation R-HSA-2186741 SMAD2/3 activation induces binding of RNF111/SMURF2 to SKI/SKIL R-HSA-8878013 RUNX2 and SMAD1 complex binds the SMAD6 gene promoter R-HSA-2176502 NEDD4L ubiquitinates SMAD2/3 R-HSA-8878178 The complex of RUNX3, SMAD3 and SMAD4 binds the CDKN1A gene promoter R-HSA-8952226 RUNX3 binds the BCL2L11 (BIM) gene R-HSA-1181150 Signaling by NODAL R-HSA-1502540 Signaling by Activin R-HSA-2173789 TGF-beta receptor signaling activates SMADs R-HSA-2173796 SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription R-HSA-201451 Signaling by BMP R-HSA-3315487 SMAD2/3 MH2 Domain Mutants in Cancer R-HSA-2173795 Downregulation of SMAD2/3:SMAD4 transcriptional activity R-HSA-5689880 Ub-specific processing proteases R-HSA-1266738 Developmental Biology R-HSA-9006936 Signaling by TGF-beta family members R-HSA-170834 Signaling by TGF-beta Receptor Complex R-HSA-2173793 Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer R-HSA-3304349 Loss of Function of SMAD2/3 in Cancer R-HSA-5688426 Deubiquitination R-HSA-8941326 RUNX2 regulates bone development R-HSA-452723 Transcriptional regulation of pluripotent stem cells R-HSA-8941855 RUNX3 regulates CDKN1A transcription R-HSA-3311021 SMAD4 MH2 Domain Mutants in Cancer R-HSA-162582 Signal Transduction R-HSA-212436 Generic Transcription Pathway R-HSA-3304351 Signaling by TGF-beta Receptor Complex in Cancer R-HSA-597592 Post-translational protein modification R-HSA-8878166 Transcriptional regulation by RUNX2 R-HSA-8952158 RUNX3 regulates BCL2L11 (BIM) transcription R-HSA-8878159 Transcriptional regulation by RUNX3 R-HSA-3304347 Loss of Function of SMAD4 in Cancer R-HSA-73857 RNA Polymerase II Transcription R-HSA-5663202 Diseases of signal transduction R-HSA-392499 Metabolism of proteins R-HSA-74160 Gene expression (Transcription) R-HSA-1643685 Disease
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
