Reviewed,
UniProtKB/Swiss-Prot Q13485 (SMAD4_HUMAN)
Last modified
November 25, 2008.
Version 102.
History...
Clusters with 100%,
90%,
50% identity |
Documents (6) |
Third-party data |
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Names and origin
| Protein names | Recommended name: Mothers against decapentaplegic homolog 4 Short name=Mothers against DPP homolog 4 Alternative name(s): SMAD 4 hSMAD4 Deletion target in pancreatic carcinoma 4 | ||||
| Gene names |
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| Organism | Homo sapiens (Human) | ||||
| Taxonomic identifier | 9606 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Protein attributes
| Sequence length | 552 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is not processed. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| Function | Common mediator of signal transduction by TGF-beta (transforming growth factor) superfamily; SMAD4 is the common SMAD (co-SMAD). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. May act as a tumor suppressor. |
| Subunit structure | May form trimers with receptor-regulated SMAD (R-SMAD). Found in a ternary complex composed of SMAD4, STK11 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11, STK11IP and TRIM33. Associates with ZNF423 or ZNF521 in response to BMP2 leading to activate transcription of BMP target genes. |
| Subcellular location | Cytoplasm. Nucleus. Note= Cytoplasmic in the absence of ligand. Migrates to the nucleus when complexed with R-SMAD. |
| Involvement in disease | Defects in SMAD4 are a cause of pancreatic carcinoma [MIM:260350]. 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. 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 aetiology of this association is unknown. Defects in SMAD4 may be a cause of colorectal cancer (CRC) [MIM:114500]. |
| Sequence similarities | Belongs to the dwarfin/SMAD family. Contains 1 MH1 (MAD homology 1) domain. Contains 1 MH2 (MAD homology 2) domain. |
Ontologies
Binary interactions
With | Entry | #Exp. | IntAct | Notes |
|---|---|---|---|---|
| CEBPB | P17676 | 1 | EBI-347263,EBI-969696 | |
| DACH1 | Q9UI36 | 3 | EBI-347263,EBI-347111 | |
| SKI | P12755 | 2 | EBI-347263,EBI-347281 |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||||||||||||||||||||||||||||||||||||||||
Molecule processing | |||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Chain | 1 – 552 | 552 | Mothers against decapentaplegic homolog 4 | PRO_0000090861 | |||||||||||||||||||||||||||||||||||||||||||
Regions | |||||||||||||||||||||||||||||||||||||||||||||||
| Domain | 18 – 142 | 125 | MH1 | ||||||||||||||||||||||||||||||||||||||||||||
| Domain | 323 – 552 | 230 | MH2 | ||||||||||||||||||||||||||||||||||||||||||||
| Region | 275 – 320 | 46 | SAD | ||||||||||||||||||||||||||||||||||||||||||||
| Compositional bias | 451 – 466 | 16 | Poly-Ala | ||||||||||||||||||||||||||||||||||||||||||||
Natural variations | |||||||||||||||||||||||||||||||||||||||||||||||
| Natural variant | 130 | 1 | P → S in a colorectal cancer sample; somatic mutation. | VAR_036475 | |||||||||||||||||||||||||||||||||||||||||||
| Natural variant | 330 | 1 | E → G in JPS. | VAR_022833 | |||||||||||||||||||||||||||||||||||||||||||
| Natural variant | 351 | 1 | D → N in a colorectal cancer sample; somatic mutation. | VAR_036476 | |||||||||||||||||||||||||||||||||||||||||||
| Natural variant | 352 | 1 | G → R in JP/HHT and JPS. | VAR_019571 | |||||||||||||||||||||||||||||||||||||||||||
| Natural variant | 361 | 1 | R → C in JPS. | VAR_019572 | |||||||||||||||||||||||||||||||||||||||||||
| Natural variant | 361 | 1 | R → H in a colorectal cancer sample; somatic mutation. | VAR_036477 | |||||||||||||||||||||||||||||||||||||||||||
| Natural variant | 386 | 1 | G → D in JP/HHT. | VAR_019573 | |||||||||||||||||||||||||||||||||||||||||||
| Natural variant | 493 | 1 | D → H in pancreatic carcinoma. | VAR_011380 | |||||||||||||||||||||||||||||||||||||||||||
Secondary structure | |||||||||||||||||||||||||||||||||||||||||||||||
Helix Strand Turn | |||||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 288 – 291 | 4 | |||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 321 – 330 | 10 | |||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 333 – 342 | 10 | |||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 346 – 353 | 8 | |||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 359 – 363 | 5 | |||||||||||||||||||||||||||||||||||||||||||||
| Helix | 374 – 380 | 7 | |||||||||||||||||||||||||||||||||||||||||||||
| Turn | 381 – 385 | 5 | |||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 387 – 392 | 6 | |||||||||||||||||||||||||||||||||||||||||||||
| Turn | 393 – 395 | 3 | |||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 396 – 401 | 6 | |||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 403 – 405 | 3 | |||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 407 – 410 | 4 | |||||||||||||||||||||||||||||||||||||||||||||
| Helix | 412 – 416 | 5 | |||||||||||||||||||||||||||||||||||||||||||||
| Turn | 417 – 419 | 3 | |||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 427 – 429 | 3 | |||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 434 – 438 | 5 | |||||||||||||||||||||||||||||||||||||||||||||
| Helix | 440 – 454 | 15 | |||||||||||||||||||||||||||||||||||||||||||||
| Helix | 493 – 497 | 5 | |||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 500 – 506 | 7 | |||||||||||||||||||||||||||||||||||||||||||||
| Helix | 518 – 520 | 3 | |||||||||||||||||||||||||||||||||||||||||||||
| Beta strand | 521 – 529 | 9 | |||||||||||||||||||||||||||||||||||||||||||||
| Helix | 530 – 541 | 12 | |||||||||||||||||||||||||||||||||||||||||||||
Sequences
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References
| « Hide 'large scale' references | |
| [1] | "DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1." Hahn S.A., Schutte M., Shamsul Hoque A.T.M., Moskaluk C.A., da Costa L.T., Rozenblum E., Weinstein C.L., Fischer A., Yeo C.J., Hruban R.H., Kern S.E. Science 271:350-353(1996) [PubMed: 8553070] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANT PANCREATIC CARCINOMA HIS-493. Tissue: Fetal brain. |
| [2] | "Receptor-associated Mad homologues synergize as effectors of the TGF-beta response." Zhang Y., Feng X.-H., Wu R.-Y., Derynck R. Nature 383:168-172(1996) [PubMed: 8774881] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Placenta. |
| [3] | "Genomic sequencing of DPC4 in the analysis of familial pancreatic carcinoma." Moskaluk C.A., Hruban R.H., Schutte M., Lietman A.S., Smyrk T., Fusaro L., Fusaro R., Lynch J., Yeo C.J., Jackson C.E., Lynch H.T., Kern S.E. Diagn. Mol. Pathol. 6:85-90(1997) [PubMed: 9098646] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. |
| [4] | "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Muscle. |
| [5] | "Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible transcriptional complexes." Liu F., Pouponnot C., Massague J. Genes Dev. 11:3157-3167(1997) [PubMed: 9389648] [Abstract] Cited for: FUNCTION. |
| [6] | "OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways." Hata A., Seoane J., Lagna G., Montalvo E., Hemmati-Brivanlou A., Massague J. Cell 100:229-240(2000) [PubMed: 10660046] [Abstract] Cited for: INTERACTION WITH ZNF423. |
| [7] | "The Smad4 activation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain." de Caestecker M.P., Yahata T., Wang D., Parks W.T., Huang S., Hill C.S., Shioda T., Roberts A.B., Lechleider R.J. J. Biol. Chem. 275:2115-2122(2000) [PubMed: 10636916] [Abstract] Cited for: CHARACTERIZATION OF SAD DOMAIN. |
| [8] | "LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1." Smith D.P., Rayter S.I., Niederlander C., Spicer J., Jones C.M., Ashworth A. Hum. Mol. Genet. 10:2869-2877(2001) [PubMed: 11741830] [Abstract] Cited for: IDENTIFICATION IN A TERNARY COMPLEX COMPOSED OF STK11 AND STK11IP, INTERACTS WITH STK11 AND STK11IP. |
| [9] | "Jab1 antagonizes TGF-beta signaling by inducing Smad4 degradation." Wan M., Cao X., Wu Y., Bai S., Wu L., Shi X., Wang N., Cao X. EMBO Rep. 3:171-176(2002) [PubMed: 11818334] [Abstract] Cited for: INTERACTION WITH COPS5. |
| [10] | "DACH1 inhibits transforming growth factor-beta signaling through binding Smad4." Wu K., Yang Y., Wang C., Davoli M.A., D'Amico M., Li A., Cveklova K., Kozmik Z., Lisanti M.P., Russell R.G., Cvekl A., Pestell R.G. J. Biol. Chem. 278:51673-51684(2003) [PubMed: 14525983] [Abstract] Cited for: INTERACTION WITH DACH1. |
| [11] | "Early hematopoietic zinc finger protein (EHZF), the human homolog to mouse Evi3, is highly expressed in primitive human hematopoietic cells." Bond H.M., Mesuraca M., Carbone E., Bonelli P., Agosti V., Amodio N., De Rosa G., Di Nicola M., Gianni A.M., Moore M.A., Hata A., Grieco M., Morrone G., Venuta S. Blood 103:2062-2070(2004) [PubMed: 14630787] [Abstract] Cited for: INTERACTION WITH ZNF521. |
| [12] | "Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase." Dupont S., Zacchigna L., Cordenonsi M., Soligo S., Adorno M., Rugge M., Piccolo S. Cell 121:87-99(2005) [PubMed: 15820681] [Abstract] Cited for: INTERACTION WITH TRIM33. |
| [13] | "A structural basis for mutational inactivation of the tumour suppressor Smad4." Shi Y., Hata A., Lo R.S., Massague J., Pavletich N.P. Nature 388:87-93(1997) [PubMed: 9214508] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 319-543. |
| [14] | "Crystal structure of a transcriptionally active Smad4 fragment." Qin B., Lam S.S., Lin K. Structure 7:1493-1503(1999) [PubMed: 10647180] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 285-552. |
| [15] | "The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization." Chacko B.M., Qin B., Correia J.J., Lam S.S., de Caestecker M.P., Lin K. Nat. Struct. Biol. 8:248-253(2001) [PubMed: 11224571] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3 ANGSTROMS) OF 273-552. |
| [16] | "TGF-beta signal transduction." Massague J. Annu. Rev. Biochem. 67:753-791(1998) [PubMed: 9759503] [Abstract] Cited for: REVIEW. |
| [17] | "Remarkable versatility of Smad proteins in the nucleus of transforming growth factor-beta activated cells." Verschueren K., Huylebroeck D. Cytokine Growth Factor Rev. 10:187-199(1999) [PubMed: 10647776] [Abstract] Cited for: REVIEW. |
| [18] | "The Smad pathway." Wrana J.L., Attisano L. Cytokine Growth Factor Rev. 11:5-13(2000) [PubMed: 10708948] [Abstract] Cited for: REVIEW. |
| [19] | "TGF-beta signaling by Smad proteins." Miyazono K. Cytokine Growth Factor Rev. 11:15-22(2000) [PubMed: 10708949] [Abstract] Cited for: REVIEW. |
| [20] | "Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases." Houlston R., Bevan S., Williams A., Young J., Dunlop M., Rozen P., Eng C., Markie D., Woodford-Richens K., Rodriguez-Bigas M.A., Leggett B., Neale K., Phillips R., Sheridan E., Hodgson S., Iwama T., Eccles D., Bodmer W., Tomlinson I. Hum. Mol. Genet. 7:1907-1912(1998) [PubMed: 9811934] [Abstract] Cited for: VARIANT JPS CYS-361. |
| [21] | "Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis." Sayed M.G., Ahmed A.F., Ringold J.R., Anderson M.E., Bair J.L., Mitros F.A., Lynch H.T., Tinley S.T., Petersen G.M., Giardiello F.M., Vogelstein B., Howe J.R. Ann. Surg. Oncol. 9:901-906(2002) [PubMed: 12417513] [Abstract] Cited for: VARIANTS JPS GLY-330 AND ARG-352. |
| [22] | "A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4)." Gallione C.J., Repetto G.M., Legius E., Rustgi A.K., Schelley S.L., Tejpar S., Mitchell G., Drouin E., Westermann C.J.J., Marchuk D.A. Lancet 363:852-859(2004) [PubMed: 15031030] [Abstract] Cited for: VARIANTS JP/HHT ARG-352 AND ASP-386. |
| [23] | "The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. Velculescu V.E.Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] SER-130; ASN-351 AND HIS-361. |
| + | Additional computationally mapped references. |
Cross-references
Sequence databases | |||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
AF045447 AF045446 Genomic DNA. Translation: AAC03051.1. U44378 mRNA. Translation: AAA91041.1. BC002379 mRNA. Translation: AAH02379.1. | |||||||||||||||||||||||||||||||||||||||||||
| PIR | S71811. | ||||||||||||||||||||||||||||||||||||||||||
| RefSeq | NP_005350.1. | ||||||||||||||||||||||||||||||||||||||||||
| UniGene | Hs.592888 Hs.75862 | ||||||||||||||||||||||||||||||||||||||||||
3D structure databases | |||||||||||||||||||||||||||||||||||||||||||
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| DisProt | DP00464. | ||||||||||||||||||||||||||||||||||||||||||
| ModBase | Search... | ||||||||||||||||||||||||||||||||||||||||||
Protein-protein interaction databases | |||||||||||||||||||||||||||||||||||||||||||
| IntAct | Q13485. | ||||||||||||||||||||||||||||||||||||||||||
PTM databases | |||||||||||||||||||||||||||||||||||||||||||
| PhosphoSite | Q13485. | ||||||||||||||||||||||||||||||||||||||||||
Proteomic databases | |||||||||||||||||||||||||||||||||||||||||||
| PeptideAtlas | Q13485. | ||||||||||||||||||||||||||||||||||||||||||
Genome annotation databases | |||||||||||||||||||||||||||||||||||||||||||
| Ensembl | ENSG00000141646. Homo sapiens. [Contig view] | ||||||||||||||||||||||||||||||||||||||||||
| GeneID | 4089. | ||||||||||||||||||||||||||||||||||||||||||
| KEGG | hsa:4089. | ||||||||||||||||||||||||||||||||||||||||||
Organism-specific databases | |||||||||||||||||||||||||||||||||||||||||||
| H-InvDB | HIX0014453. | ||||||||||||||||||||||||||||||||||||||||||
| HGNC | HGNC:6770. SMAD4. | ||||||||||||||||||||||||||||||||||||||||||
| HPA | CAB002312 | ||||||||||||||||||||||||||||||||||||||||||

Clusters with