Reviewed,
UniProtKB/Swiss-Prot O15105 (SMAD7_HUMAN)
Last modified
June 16, 2009.
Version 93.
History...
Clusters with 100%,
90%,
50% identity |
Documents (4) |
Third-party data |
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Names and origin
| Protein names | Recommended name: Mothers against decapentaplegic homolog 7 Short name=Mothers against DPP homolog 7 Alternative name(s): SMAD 7 Short name=Smad7 hSMAD7 | ||||
| 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 | 426 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is not processed. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| Function | Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access. Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1, which promotes its dephosphorylation. Ref.10 Ref.14 |
| Subunit structure | Interacts with TGF-beta type I receptor. Interacts with COPS5. Interacts with NEDD4L. Interacts with STAMBP. Interacts with RNF111, AXIN1 and AXIN2. Interacts with PPP1R15A. Interacts (via MH2 domain) with EP300. Interacts with SMURF2. Ref.14 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17 |
| Subcellular location | Nucleus. Cytoplasm. Note: Interaction with NEDD4L or RNF111 induces translocation from the nucleus to the cytoplasm. Ref.13 Ref.17 |
| Tissue specificity | Ubiquitous with higher expression in the lung and vascular endothelium. |
| Induction | By TGF-beta. |
| Post-translational modification | Phosphorylation on Ser-249 does not affect its stability, nuclear localization or inhibitory function in TGFB signaling; however it affects its ability to regulate transcription By similarity. Polyubiquitinated by RNF111, which is enhanced by AXIN1 and promotes proteasomal degradation. In response to TGF-beta, ubiquitinated by SMURF1; which promotes its degradation. Acetylation prevents ubiquitination and degradation mediated by SMURF1. |
| Involvement in disease | Genetic variations in SMAD7 influence susceptibility to colorectal cancer type 3 (CRCS3) [MIM:612229]. Colorectal cancer consists of tumors or cancer of either the colon or rectum or both. Cancers of the large intestine are the second most common form of cancer found in males and females. Symptoms include rectal bleeding, occult blood in stools, bowel obstruction and weight loss. Treatment is based largely on the extent of cancer penetration into the intestinal wall. Surgical cures are possible if the malignancy is confined to the intestine. Risk can be reduced when following a diet which is low in fat and high in fiber. Ref.19 |
| Sequence similarities | Belongs to the dwarfin/SMAD family. Contains 1 MH1 (MAD homology 1) domain. Contains 1 MH2 (MAD homology 2) domain. |
Ontologies
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||||||
Molecule processing | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Chain | 1 – 426 | 426 | Mothers against decapentaplegic homolog 7 | PRO_0000090872 | |||||||||
Regions | |||||||||||||
| Domain | 64 – 207 | 144 | MH1 | ||||||||||
| Domain | 261 – 426 | 166 | MH2 | ||||||||||
| Region | 208 – 217 | 10 | Important for interaction with SMURF2 | ||||||||||
| Motif | 208 – 211 | 4 | PY-motif | ||||||||||
| Compositional bias | 27 – 35 | 9 | Poly-Gly | ||||||||||
| Compositional bias | 49 – 56 | 8 | Poly-Gly | ||||||||||
| Compositional bias | 207 – 210 | 4 | Poly-Pro | ||||||||||
Amino acid modifications | |||||||||||||
| Modified residue | 64 | 1 | N6-acetyllysine; alternate Ref.12 | ||||||||||
| Modified residue | 70 | 1 | N6-acetyllysine; alternate Ref.12 | ||||||||||
| Modified residue | 249 | 1 | Phosphoserine By similarity | ||||||||||
| Cross-link | 64 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate Ref.12 | |||||||||||
| Cross-link | 70 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate Ref.12 | |||||||||||
Experimental info | |||||||||||||
| Mutagenesis | 64 | 1 | K → A: Loss of acetylation, and of SMURF1-dependent degradation; when associated with A-70. Ref.12 | ||||||||||
| Mutagenesis | 70 | 1 | K → A: Loss of acetylation, and of SMURF1-dependent degradation; when associated with A-64. Ref.12 | ||||||||||
| Mutagenesis | 207 – 211 | 5 | Missing: Diminishes interaction with SMURF2. Ref.10 | ||||||||||
| Mutagenesis | 211 | 1 | Y → A: Diminishes interaction with SMURF2 and reduces inhibition of TGF-beta signaling. Ref.10 | ||||||||||
| Mutagenesis | 409 – 426 | 18 | Missing: 90% reduction in TGF-beta receptor binding. Ref.1 | ||||||||||
| Sequence conflict | 71 | 1 | G → C in AAB81354. Ref.3 | ||||||||||
Secondary structure | |||||||||||||
Helix Strand Turn | |||||||||||||
| Beta strand | 204 – 206 | 3 | |||||||||||
| Beta strand | 212 – 214 | 3 | |||||||||||
Sequences
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References
| « Hide 'large scale' references | |
| [1] | "The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling." Hayashi H., Abdollah S., Qiu Y., Cai J., Xu Y.-Y., Grinnell B.W., Richardson M.A., Topper J.N., Gimbrone M.A. Jr., Wrana J.L., Falb D. Cell 89:1165-1173(1997) [PubMed: 9215638] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF 409-ARG--ARG-426. Tissue: Umbilical vein endothelial cell. |
| [2] | "Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium." Topper J.N., Cai J., Qui Y., Anderson K.R., Xu Y.-Y., Deeds J.D., Feeley R., Gimeno C.J., Woolf E.A., Tayber O., Mays G.G., Sampson B.A., Schoen F.J., Gimbrone M.A. Jr., Falb D. Proc. Natl. Acad. Sci. U.S.A. 94:9314-9319(1997) [PubMed: 9256479] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Umbilical vein endothelial cell. |
| [3] | "Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling." Nakao A., Afrakhte M., Moren A., Nakayama T., Christian J.L., Heuchel R., Itoh S., Kawabata M., Heldin N.-E., Heldin C.-H., ten Dijke P. Nature 389:631-635(1997) [PubMed: 9335507] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain. |
| [4] | Hagiwara K., Yang K., McMenamin M.G., Freeman A.H., Bennett W.P., Nagashima M., Minter A.R., Miyazono K., Takenoshita S., Harris C.C. Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. |
| [5] | "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: Lung. |
| [6] | "TGF-beta signal transduction." Massague J. Annu. Rev. Biochem. 67:753-791(1998) [PubMed: 9759503] [Abstract] Cited for: REVIEW. |
| [7] | "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. |
| [8] | "The Smad pathway." Wrana J.L., Attisano L. Cytokine Growth Factor Rev. 11:5-13(2000) [PubMed: 10708948] [Abstract] Cited for: REVIEW. |
| [9] | "TGF-beta signaling by Smad proteins." Miyazono K. Cytokine Growth Factor Rev. 11:15-22(2000) [PubMed: 10708949] [Abstract] Cited for: REVIEW. |
| [10] | "Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF-beta receptor for degradation." Kavsak P., Rasmussen R.K., Causing C.G., Bonni S., Zhu H., Thomsen G.H., Wrana J.L. Mol. Cell 6:1365-1375(2000) [PubMed: 11163210] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF TYR-211 AND 207-PRO--TYR-211. |
| [11] | "Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads." Itoh F., Asao H., Sugamura K., Heldin C.-H., ten Dijke P., Itoh S. EMBO J. 20:4132-4142(2001) [PubMed: 11483516] [Abstract] Cited for: INTERACTION WITH STAMBP. |
| [12] | "Control of Smad7 stability by competition between acetylation and ubiquitination." Gronroos E., Hellman U., Heldin C.H., Ericsson J. Mol. Cell 10:483-493(2002) [PubMed: 12408818] [Abstract] Cited for: INTERACTION WITH EP300, ACETYLATION AT LYS-64 AND LYS-70, UBIQUITINATION AT LYS-64 AND LYS-70, MUTAGENESIS OF LYS-64 AND LYS-70. |
| [13] | "Arkadia amplifies TGF-beta superfamily signaling through degradation of Smad7." Koinuma D., Shinozaki M., Komuro A., Goto K., Saitoh M., Hanyu A., Ebina M., Nukiwa T., Miyazawa K., Imamura T., Miyazono K. EMBO J. 22:6458-6470(2003) [PubMed: 14657019] [Abstract] Cited for: INTERACTION WITH RNF111, UBIQUITINATION, SUBCELLULAR LOCATION. |
| [14] | "GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor." Shi W., Sun C., He B., Xiong W., Shi X., Yao D., Cao X. J. Cell Biol. 164:291-300(2004) [PubMed: 14718519] [Abstract] Cited for: FUNCTION, INTERACTION WITH PPP1R15A. |
| [15] | "Jab1/CSN5, a component of the COP9 signalosome, regulates transforming growth factor beta signaling by binding to Smad7 and promoting its degradation." Kim B.-C., Lee H.-J., Park S.H., Lee S.R., Karpova T.S., McNally J.G., Felici A., Lee D.K., Kim S.-J. Mol. Cell. Biol. 24:2251-2262(2004) [PubMed: 14993265] [Abstract] Cited for: INTERACTION WITH COPS5. |
| [16] | "Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain." Ogunjimi A.A., Briant D.J., Pece-Barbara N., Le Roy C., Di Guglielmo G.M., Kavsak P., Rasmussen R.K., Seet B.T., Sicheri F., Wrana J.L. Mol. Cell 19:297-308(2005) [PubMed: 16061177] [Abstract] Cited for: INTERACTION WITH SMURF2. |
| [17] | "Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia." Liu W., Rui H., Wang J., Lin S., He Y., Chen M., Li Q., Ye Z., Zhang S., Chan S.C., Chen Y.-G., Han J., Lin S.-C. EMBO J. 25:1646-1658(2006) [PubMed: 16601693] [Abstract] Cited for: INTERACTION WITH AXIN1 AND AXIN2, UBIQUITINATION, SUBCELLULAR LOCATION. |
| [18] | "An expanded WW domain recognition motif revealed by the interaction between Smad7 and the E3 ubiquitin ligase Smurf2." Chong P.A., Lin H., Wrana J.L., Forman-Kay J.D. J. Biol. Chem. 281:17069-17075(2006) [PubMed: 16641086] [Abstract] Cited for: STRUCTURE BY NMR OF 203-217 IN COMPLEX WITH SMURF2. |
| [19] | "A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk." Members of the CORGI consortium Broderick P., Carvajal-Carmona L., Pittman A.M., Webb E., Howarth K., Rowan A., Lubbe S., Spain S., Sullivan K., Fielding S., Jaeger E., Vijayakrishnan J., Kemp Z., Gorman M., Chandler I., Papaemmanuil E., Penegar S., Wood W. Houlston R.S.Nat. Genet. 39:1315-1317(2007) [PubMed: 17934461] [Abstract] Cited for: INVOLVEMENT IN CRCS3. |
Cross-references
Sequence databases | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AF010193 mRNA. Translation: AAB81246.1. AF015261 mRNA. Translation: AAB81354.1. AF026559 AF026558 Genomic DNA. Translation: AAL68977.1. BC074818 mRNA. Translation: AAH74818.2. BC074819 mRNA. Translation: AAH74819.2. | |||||||||||||
| IPI | IPI00005079. | ||||||||||||
| RefSeq | NP_005895.1. | ||||||||||||
| UniGene | Hs.465087 | ||||||||||||
3D structure databases | |||||||||||||
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| ModBase | Search... | ||||||||||||
PTM databases | |||||||||||||
| PhosphoSite | O15105. | ||||||||||||
Proteomic databases | |||||||||||||
| PRIDE | O15105. | ||||||||||||
Genome annotation databases | |||||||||||||
| Ensembl | ENSG00000101665. Homo sapiens. [Contig view] | ||||||||||||
| GeneID | 4092. | ||||||||||||
| KEGG | hsa:4092. | ||||||||||||
Organism-specific databases | |||||||||||||
| GeneCards | GC18M044700. | ||||||||||||
| H-InvDB | HIX0039705. | ||||||||||||
| HGNC | HGNC:6773. SMAD7. | ||||||||||||
| MIM | 602932. gene. 612229. phenotype. | ||||||||||||
| PharmGKB | PA134875286. | ||||||||||||
| GenAtlas | Search... | ||||||||||||
Phylogenomic databases | |||||||||||||
| HOGENOM | O15105. | ||||||||||||
| HOVERGEN | O15105. | ||||||||||||
| OMA | O15105. SAYSLPL. | ||||||||||||
Enzyme and pathway databases | |||||||||||||
| Pathway_Interaction_DB | bmppathway. BMP receptor signaling. ifngpathway. IFN-gamma pathway. smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling. hdac_classi_pathway. Signaling events mediated by HDAC Class I. tgfbrpathway. TGF-beta receptor signaling. | ||||||||||||
| Reactome | REACT_12034. Signaling by BMP. REACT_6844. Signaling by TGF beta. | ||||||||||||
Gene expression databases | |||||||||||||
| ArrayExpress | O15105. | ||||||||||||
| Bgee | O15105. | ||||||||||||
| CleanEx | HS_SMAD7. | ||||||||||||
| GermOnline | ENSG00000101665. Homo sapiens. | ||||||||||||
Family and domain databases | |||||||||||||
| InterPro | IPR013790. Dwarfin. IPR003619. MAD_homology1_Dwarfin-type. IPR013019. MAD_homology_MH1. IPR017855. SMAD_dom-like. IPR001132. SMAD_dom_Dwarfin-type. [Graphical view] | ||||||||||||
| Gene3D | G3DSA:3.90.520.10. MAD_MH1. 1 hit. G3DSA:2.60.200.10. MH2_Dwarfin-type. 1 hit. | ||||||||||||
| PANTHER | PTHR13703. Dwarfin. 1 hit. | ||||||||||||
| Pfam | PF03165. MH1. 1 hit. PF03166. MH2. 1 hit. [Graphical view] | ||||||||||||
| SMART | SM00523. DWA. 1 hit. SM00524. DWB. 1 hit. [Graphical view] | ||||||||||||
| PROSITE | PS51075. MH1. 1 hit. PS51076. MH2. 1 hit. [Graphical view] | ||||||||||||
| ProtoNet | Search... | ||||||||||||
Other Resources | |||||||||||||
| NextBio | 16046. | ||||||||||||
| SOURCE | Search... | ||||||||||||
Entry information
| Entry name | SMAD7_HUMAN | ||||||||
| Accession | Primary (citable) accession number: O15105 Secondary accession number(s): O14740, Q6DK23 | ||||||||
| Entry history |
| ||||||||
| Entry status | Reviewed (UniProtKB/Swiss-Prot) | ||||||||
| Annotation project | HPI (Human Proteome Initiative) | ||||||||
Relevant documents
| Human chromosome 18 Human chromosome 18: entries, gene names and cross-references to MIM |
| MIM cross-references Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot |
| PDB cross-references Index of Protein Data Bank (PDB) cross-references |
| SIMILARITY comments Index of protein domains and families |

Clusters with


