Mothers against decapentaplegic homolog 2

SMAD family member 2
PDB rendering based on 1dev.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1DEV​, 1KHX​, 1U7V​, 2LB3​
Identifiers
Symbols	SMAD2 ; JV18; JV18-1; MADH2; MADR2; hMAD-2; hSMAD2
External IDs	OMIM: 601366 MGI: 108051 HomoloGene: 21197 GeneCards: SMAD2 Gene
Gene ontology Molecular function • RNA polymerase II core promoter proximal region sequence-specific DNA binding • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding • DNA binding • chromatin binding • double-stranded DNA binding • transcription factor activity, sequence-specific DNA binding • transforming growth factor beta receptor binding • protein binding • transcription factor binding • phosphatase binding • transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity • ubiquitin protein ligase binding • activating transcription factor binding • type I transforming growth factor beta receptor binding • enhancer binding • protein homodimerization activity • SMAD binding • metal ion binding • protein heterodimerization activity • co-SMAD binding • I-SMAD binding • R-SMAD binding Cellular component • nuclear chromatin • nucleus • nucleoplasm • transcription factor complex • cytoplasm • cytosol • activin responsive factor complex • SMAD protein complex • SMAD2-SMAD3 protein complex Biological process • negative regulation of transcription from RNA polymerase II promoter • ureteric bud development • in utero embryonic development • endoderm formation • mesoderm formation • transcription, DNA-templated • transcription initiation from RNA polymerase II promoter • transforming growth factor beta receptor signaling pathway • common-partner SMAD protein phosphorylation • SMAD protein complex assembly • zygotic specification of dorsal/ventral axis • gastrulation • response to glucose • post-embryonic development • anterior/posterior pattern specification • gene expression • positive regulation of epithelial to mesenchymal transition • regulation of transforming growth factor beta receptor signaling pathway • insulin secretion • lung development • negative regulation of transforming growth factor beta receptor signaling pathway • positive regulation of BMP signaling pathway • pancreas development • primary miRNA processing • activin receptor signaling pathway • somatic stem cell maintenance • organ growth • intracellular signal transduction • nodal signaling pathway • cell fate commitment • negative regulation of transcription, DNA-templated • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • paraxial mesoderm morphogenesis • embryonic foregut morphogenesis • embryonic cranial skeleton morphogenesis • regulation of binding • palate development • pericardium development • SMAD protein signal transduction • response to cholesterol • positive regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4087	17126
Ensembl	ENSG00000175387	ENSMUSG00000024563
UniProt	Q15796	Q62432
RefSeq (mRNA)	NM_001003652	NM_001252481
RefSeq (protein)	NP_001003652	NP_001239410
Location (UCSC)	Chr 18: 47.81 – 47.93 Mb	Chr 18: 76.24 – 76.31 Mb
PubMed search

Mothers against decapentaplegic homolog 2 also known as SMAD family member 2 or SMAD2 is a protein that in humans is encoded by the SMAD2 gene.^[1][2] MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways.

Function

SMAD2 mediates the signal of the transforming growth factor (TGF)-beta, and thus regulates multiple cellular processes, such as cell proliferation, apoptosis, and differentiation. This protein is recruited to the TGF-beta receptors through its interaction with the SMAD anchor for receptor activation (SARA) protein. In response to TGF-beta signal, this protein is phosphorylated by the TGF-beta receptors. The phosphorylation induces the dissociation of this protein with SARA and the association with the family member SMAD4. The association with SMAD4 is important for the translocation of this protein into the cell nucleus, where it binds to target promoters and forms a transcription repressor complex with other cofactors. This protein can also be phosphorylated by activin type 1 receptor kinase, and mediates the signal from the activin. Alternatively spliced transcript variants encoding the same protein have been observed.^[3]

Like other Smads, Smad2 plays a role in the transmission of extracellular signals from ligands of the Transforming Growth Factor beta (TGFβ) superfamily of growth factors into the cell nucleus. Binding of a subgroup of TGFβ superfamily ligands to extracellular receptors triggers phosphorylation of Smad2 at a Serine-Serine-Methionine-Serine (SSMS) motif at its extreme C-terminus. Phosphorylated Smad2 is then able to form a complex with Smad4. These complexes accumulate in the cell nucleus, where they are directly participating in the regulation of gene expression.

Nomenclature

The SMAD proteins are homologs of both the drosophila protein, mothers against decapentaplegic (MAD) and the C. elegans protein SMA. The name is a combination of the two. During Drosophila research, it was found that a mutation in the gene MAD in the mother repressed the gene decapentaplegic in the embryo. The phrase "Mothers against" was added, since mothers often form organizations opposing various issues, e.g., Mothers Against Drunk Driving, or (MADD). The nomenclature for this protein, like that of Sonic hedgehog, has been criticized for its frivolity

Interactions

Mothers against decapentaplegic homolog 2 has been shown to interact with:

• ANAPC10,^[4]
• DAB2,^[5]
• EP300,^[6][7]
• FOXH1,^{[6][8][9][10][11]}
• HDAC1,^[6]
• TGIF1,^[6][7]
• Insulin receptor,^[12]
• LEF1,^[13]
• Myc,^[14]
• MEF2A,^[15]
• PIAS3,^[16]
• PIN1,^[17]
• SKI protein,^[18][19]
• SKIL,^[20][21]
• SMAD3,^[22][23]
• SMURF2,^[17][24][25]
• SNW1,^[26]
• STRAP^[27]

References

1. Eppert K, Scherer SW, Ozcelik H, Pirone R, Hoodless P, Kim H, Tsui LC, Bapat B, Gallinger S, Andrulis IL, Thomsen GH, Wrana JL, Attisano L (August 1996). "MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma". Cell 86 (4): 543–52. doi:10.1016/S0092-8674(00)80128-2. PMID 8752209.
2. Riggins GJ, Thiagalingam S, Rozenblum E, Weinstein CL, Kern SE, Hamilton SR, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B (July 1996). "Mad-related genes in the human". Nat. Genet. 13 (3): 347–9. doi:10.1038/ng0796-347. PMID 8673135.
3. "Entrez Gene: SMAD2 SMAD family member 2".
4. Nourry C, Maksumova L, Pang M, Liu X, Wang T (May 2004). "Direct interaction between Smad3, APC10, CDH1 and HEF1 in proteasomal degradation of HEF1". BMC Cell Biol. 5: 20. doi:10.1186/1471-2121-5-20. PMC 420458. PMID 15144564.
5. Hocevar BA, Smine A, Xu XX, Howe PH (June 2001). "The adaptor molecule Disabled-2 links the transforming growth factor β receptors to the Smad pathway". EMBO J. 20 (11): 2789–801. doi:10.1093/emboj/20.11.2789. ISSN 0261-4189. PMC 125498. PMID 11387212.
6. Wotton D, Lo RS, Lee S, Massagué J (April 1999). "A Smad transcriptional corepressor". Cell 97 (1): 29–39. doi:10.1016/S0092-8674(00)80712-6. ISSN 0092-8674. PMID 10199400.
7. Pessah M, Prunier C, Marais J, Ferrand N, Mazars A, Lallemand F, Gauthier JM, Atfi A (May 2001). "c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity". Proc. Natl. Acad. Sci. U.S.A. 98 (11): 6198–203. doi:10.1073/pnas.101579798. ISSN 0027-8424. PMC 33445. PMID 11371641.
8. Liu B, Dou CL, Prabhu L, Lai E (January 1999). "FAST-2 Is a Mammalian Winged-Helix Protein Which Mediates Transforming Growth Factor β Signals". Mol. Cell. Biol. 19 (1): 424–30. ISSN 0270-7306. PMC 83900. PMID 9858566.
9. Liu F, Pouponnot C, Massagué J (December 1997). "Dual role of the Smad4/DPC4 tumor suppressor in TGFβ-inducible transcriptional complexes". Genes Dev. 11 (23): 3157–67. doi:10.1101/gad.11.23.3157. ISSN 0890-9369. PMC 316747. PMID 9389648.
10. Dou C, Lee J, Liu B, Liu F, Massague J, Xuan S, Lai E (September 2000). "BF-1 Interferes with Transforming Growth Factor β Signaling by Associating with Smad Partners". Mol. Cell. Biol. 20 (17): 6201–11. doi:10.1128/MCB.20.17.6201-6211.2000. ISSN 0270-7306. PMC 86095. PMID 10938097.
11. Chen X, Weisberg E, Fridmacher V, Watanabe M, Naco G, Whitman M (September 1997). "Smad4 and FAST-1 in the assembly of activin-responsive factor". Nature 389 (6646): 85–9. doi:10.1038/38008. ISSN 0028-0836. PMID 9288972.
12. O'Neill TJ, Zhu Y, Gustafson TA (April 1997). "Interaction of MAD2 with the carboxyl terminus of the insulin receptor but not with the IGFIR. Evidence for release from the insulin receptor after activation". J. Biol. Chem. 272 (15): 10035–40. doi:10.1074/jbc.272.15.10035. ISSN 0021-9258. PMID 9092546.
13. Labbé E, Letamendia A, Attisano L (July 2000). "Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-β and Wnt pathways". Proc. Natl. Acad. Sci. U.S.A. 97 (15): 8358–63. doi:10.1073/pnas.150152697. ISSN 0027-8424. PMC 26952. PMID 10890911.
14. Feng XH, Liang YY, Liang M, Zhai W, Lin X (January 2002). "Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGF-beta-mediated induction of the CDK inhibitor p15(Ink4B)". Mol. Cell 9 (1): 133–43. doi:10.1016/S1097-2765(01)00430-0. ISSN 1097-2765. PMID 11804592.
15. Quinn ZA, Yang CC, Wrana JL, McDermott JC (February 2001). "Smad proteins function as co-modulators for MEF2 transcriptional regulatory proteins". Nucleic Acids Res. 29 (3): 732–42. doi:10.1093/nar/29.3.732. PMC 30396. PMID 11160896.
16. Long J, Wang G, Matsuura I, He D, Liu F (January 2004). "Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3)". Proc. Natl. Acad. Sci. U.S.A. 101 (1): 99–104. doi:10.1073/pnas.0307598100. ISSN 0027-8424. PMC 314145. PMID 14691252.
17. Nakano A, Koinuma D, Miyazawa K, Uchida T, Saitoh M, Kawabata M, Hanai J, Akiyama H, Abe M, Miyazono K, Matsumoto T, Imamura T (March 2009). "Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins". J. Biol. Chem. 284 (10): 6109–15. doi:10.1074/jbc.M804659200. ISSN 0021-9258. PMID 19122240.
18. Harada J, Kokura K, Kanei-Ishii C, Nomura T, Khan MM, Kim Y, Ishii S (October 2003). "Requirement of the co-repressor homeodomain-interacting protein kinase 2 for ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation". J. Biol. Chem. 278 (40): 38998–9005. doi:10.1074/jbc.M307112200. ISSN 0021-9258. PMID 12874272.
19. Luo K, Stroschein SL, Wang W, Chen D, Martens E, Zhou S, Zhou Q (September 1999). "The Ski oncoprotein interacts with the Smad proteins to repress TGFβ signaling". Genes Dev. 13 (17): 2196–206. doi:10.1101/gad.13.17.2196. ISSN 0890-9369. PMC 316985. PMID 10485843.
20. Stroschein SL, Bonni S, Wrana JL, Luo K (November 2001). "Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN". Genes Dev. 15 (21): 2822–36. doi:10.1101/gad.912901. ISSN 0890-9369. PMC 312804. PMID 11691834.
21. Stroschein SL, Wang W, Zhou S, Zhou Q, Luo K (October 1999). "Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein". Science 286 (5440): 771–4. doi:10.1126/science.286.5440.771. ISSN 0036-8075. PMID 10531062.
22. Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, Tamaki K, Hanai J, Heldin CH, Miyazono K, ten Dijke P (September 1997). "TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4". EMBO J. 16 (17): 5353–62. doi:10.1093/emboj/16.17.5353. ISSN 0261-4189. PMC 1170167. PMID 9311995.
23. Lebrun JJ, Takabe K, Chen Y, Vale W (January 1999). "Roles of pathway-specific and inhibitory Smads in activin receptor signaling". Mol. Endocrinol. 13 (1): 15–23. doi:10.1210/mend.13.1.0218. ISSN 0888-8809. PMID 9892009.
24. Lin X, Liang M, Feng XH (November 2000). "Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling". J. Biol. Chem. 275 (47): 36818–22. doi:10.1074/jbc.C000580200. ISSN 0021-9258. PMID 11016919.
25. Bonni S, Wang HR, Causing CG, Kavsak P, Stroschein SL, Luo K, Wrana JL (June 2001). "TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation". Nat. Cell Biol. 3 (6): 587–95. doi:10.1038/35078562. ISSN 1465-7392. PMID 11389444.
26. Leong GM, Subramaniam N, Figueroa J, Flanagan JL, Hayman MJ, Eisman JA, Kouzmenko AP (May 2001). "Ski-interacting protein interacts with Smad proteins to augment transforming growth factor-beta-dependent transcription". J. Biol. Chem. 276 (21): 18243–8. doi:10.1074/jbc.M010815200. ISSN 0021-9258. PMID 11278756.
27. Datta PK, Moses HL (May 2000). "STRAP and Smad7 Synergize in the Inhibition of Transforming Growth Factor β Signaling". Mol. Cell. Biol. 20 (9): 3157–67. doi:10.1128/MCB.20.9.3157-3167.2000. ISSN 0270-7306. PMC 85610. PMID 10757800.

Further reading

• Wrana JL (1998). "TGF-beta receptors and signalling mechanisms". Mineral and electrolyte metabolism 24 (2–3): 120–30. doi:10.1159/000057359. PMID 9525694.
• Massagué J (1998). "TGF-beta signal transduction". Annu. Rev. Biochem. 67: 753–91. doi:10.1146/annurev.biochem.67.1.753. PMID 9759503.
• Verschueren K, Huylebroeck D (2000). "Remarkable versatility of Smad proteins in the nucleus of transforming growth factor-beta activated cells". Cytokine Growth Factor Rev. 10 (3–4): 187–99. doi:10.1016/S1359-6101(99)00012-X. PMID 10647776.
• Wrana JL, Attisano L (2000). "The Smad pathway". Cytokine Growth Factor Rev. 11 (1–2): 5–13. doi:10.1016/S1359-6101(99)00024-6. PMID 10708948.
• Miyazono K (2000). "TGF-beta signaling by Smad proteins". Cytokine Growth Factor Rev. 11 (1–2): 15–22. doi:10.1016/S1359-6101(99)00025-8. PMID 10708949.
• Zannis VI, Kan HY, Kritis A, Zanni E, Kardassis D (March 2001). "Transcriptional regulation of the human apolipoprotein genes". Front. Biosci. 6: D456–504. doi:10.2741/Zannis. PMID 11229886.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.