Mothers against decapentaplegic homolog 2 explained

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 is based on a tradition of such unusual naming within the gene research community.^[4]

Interactions

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

• ANAPC10,^[5]
• DAB2,^[6]
• EP300,
• FOXH1,^{[7] [8] [9] [10]}
• HDAC1,
• TGIF1,^{[11] [12]}
• Insulin receptor,^[13]
• LEF1,^[14]
• Myc,^[15]
• MEF2A,^[16]
• PIAS3,^[17]
• PIN1,^[18]
• SKI protein,^{[19] [20]}
• SKIL,^{[21] [22]}
• SMAD3,^{[23] [24]}
• SMURF2,^{[18] [25] [26]}
• SNW1,^[27]
• STRAP^[28]
• WWTR1

Further reading

• Wrana JL . TGF-beta receptors and signalling mechanisms . Mineral and Electrolyte Metabolism . 24 . 2–3 . 120–30 . 1998 . 9525694 . 10.1159/000057359 . 84458561 .
• Massagué J . TGF-beta signal transduction . Annu. Rev. Biochem. . 67 . 753–91 . 1998 . 9759503 . 10.1146/annurev.biochem.67.1.753 . free .
• Verschueren K, Huylebroeck D . Remarkable versatility of Smad proteins in the nucleus of transforming growth factor-beta activated cells . Cytokine Growth Factor Rev. . 10 . 3–4 . 187–99 . 2000 . 10647776 . 10.1016/S1359-6101(99)00012-X .
• Wrana JL, Attisano L . The Smad pathway . Cytokine Growth Factor Rev. . 11 . 1–2 . 5–13 . 2000 . 10708948 . 10.1016/S1359-6101(99)00024-6 .
• Miyazono K . TGF-beta signaling by Smad proteins . Cytokine Growth Factor Rev. . 11 . 1–2 . 15–22 . 2000 . 10708949 . 10.1016/S1359-6101(99)00025-8 .
• Zannis VI, Kan HY, Kritis A, Zanni E, Kardassis D . Transcriptional regulation of the human apolipoprotein genes . Front. Biosci. . 6 . D456–504 . March 2001 . 11229886 . 10.2741/Zannis . free .

Notes and 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 . MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma . Cell . 86 . 4 . 543–52 . August 1996 . 8752209 . 10.1016/S0092-8674(00)80128-2 . 531842 . free .
2. Riggins GJ, Thiagalingam S, Rozenblum E, Weinstein CL, Kern SE, Hamilton SR, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B . Mad-related genes in the human . Nat. Genet. . 13 . 3 . 347–9 . July 1996 . 8673135 . 10.1038/ng0796-347 . 10124489 .
3. Web site: Entrez Gene: SMAD2 SMAD family member 2.
4. https://psmag.com/sonic-hedgehog-dicer-and-the-problem-with-naming-genes-113c58df8f7a#.os08udsyk "Sonic Hedgehog, DICER, and the Problem With Naming Genes"
5. Nourry C, Maksumova L, Pang M, Liu X, Wang T . Direct interaction between Smad3, APC10, CDH1 and HEF1 in proteasomal degradation of HEF1 . BMC Cell Biol. . 5 . 20 . May 2004 . 15144564 . 420458 . 10.1186/1471-2121-5-20 . free .
6. Hocevar BA, Smine A, Xu XX, Howe PH . The adaptor molecule Disabled-2 links the transforming growth factor β receptors to the Smad pathway . EMBO J. . 20 . 11 . 2789–801 . June 2001 . 11387212 . 125498 . 10.1093/emboj/20.11.2789 . 0261-4189 .
7. Liu B, Dou CL, Prabhu L, Lai E . FAST-2 Is a Mammalian Winged-Helix Protein Which Mediates Transforming Growth Factor β Signals . Mol. Cell. Biol. . 19 . 1 . 424–30 . January 1999 . 9858566 . 83900 . 0270-7306 . 10.1128/MCB.19.1.424 .
8. Liu F, Pouponnot C, Massagué J . Dual role of the Smad4/DPC4 tumor suppressor in TGFβ-inducible transcriptional complexes . Genes Dev. . 11 . 23 . 3157–67 . December 1997 . 9389648 . 316747 . 10.1101/gad.11.23.3157 . 0890-9369 .
9. Dou C, Lee J, Liu B, Liu F, Massague J, Xuan S, Lai E . BF-1 Interferes with Transforming Growth Factor β Signaling by Associating with Smad Partners . Mol. Cell. Biol. . 20 . 17 . 6201–11 . September 2000 . 10938097 . 86095 . 10.1128/MCB.20.17.6201-6211.2000 . 0270-7306 .
10. Chen X, Weisberg E, Fridmacher V, Watanabe M, Naco G, Whitman M . Smad4 and FAST-1 in the assembly of activin-responsive factor . . 389 . 6646 . 85–9 . September 1997 . 9288972 . 10.1038/38008 . 1997Natur.389...85C . 11927346 . 0028-0836 .
11. Wotton D, Lo RS, Lee S, Massagué J . A Smad transcriptional corepressor . Cell . 97 . 1 . 29–39 . April 1999 . 10199400 . 10.1016/S0092-8674(00)80712-6 . 6907878 . 0092-8674 . free .
12. Pessah M, Prunier C, Marais J, Ferrand N, Mazars A, Lallemand F, Gauthier JM, Atfi A . c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity . . 98 . 11 . 6198–203 . May 2001 . 11371641 . 33445 . 10.1073/pnas.101579798 . 2001PNAS...98.6198P . 0027-8424 . free .
13. O'Neill TJ, Zhu Y, Gustafson TA . 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 . April 1997 . 9092546 . 10.1074/jbc.272.15.10035 . 0021-9258 . free .
14. Labbé E, Letamendia A, Attisano L . 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 . . 97 . 15 . 8358–63 . July 2000 . 10890911 . 26952 . 10.1073/pnas.150152697 . 2000PNAS...97.8358L . 0027-8424 . free .
15. Feng XH, Liang YY, Liang M, Zhai W, Lin X . 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 . January 2002 . 11804592 . 10.1016/S1097-2765(01)00430-0 . 1097-2765 . free .
16. Quinn ZA, Yang CC, Wrana JL, McDermott JC . Smad proteins function as co-modulators for MEF2 transcriptional regulatory proteins . Nucleic Acids Res. . 29 . 3 . 732–42 . February 2001 . 11160896 . 30396 . 10.1093/nar/29.3.732 .
17. Long J, Wang G, Matsuura I, He D, Liu F . Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3) . . 101 . 1 . 99–104 . January 2004 . 14691252 . 314145 . 10.1073/pnas.0307598100 . 2004PNAS..101...99L . 0027-8424 . free .
18. Nakano A, Koinuma D, Miyazawa K, Uchida T, Saitoh M, Kawabata M, Hanai J, Akiyama H, Abe M, Miyazono K, Matsumoto T, Imamura T . Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins . J. Biol. Chem. . 284 . 10 . 6109–15 . March 2009 . 19122240 . 10.1074/jbc.M804659200 . 0021-9258 . free .
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20. Luo K, Stroschein SL, Wang W, Chen D, Martens E, Zhou S, Zhou Q . The Ski oncoprotein interacts with the Smad proteins to repress TGFβ signaling . Genes Dev. . 13 . 17 . 2196–206 . September 1999 . 10485843 . 316985 . 10.1101/gad.13.17.2196 . 0890-9369 .
21. Stroschein SL, Bonni S, Wrana JL, Luo K . Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN . Genes Dev. . 15 . 21 . 2822–36 . November 2001 . 11691834 . 312804 . 10.1101/gad.912901 . 0890-9369 .
22. Stroschein SL, Wang W, Zhou S, Zhou Q, Luo K . Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein . . 286 . 5440 . 771–4 . October 1999 . 10531062 . 10.1126/science.286.5440.771 . 0036-8075 .
23. Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, Tamaki K, Hanai J, Heldin CH, Miyazono K, ten Dijke P . TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4 . EMBO J. . 16 . 17 . 5353–62 . September 1997 . 9311995 . 1170167 . 10.1093/emboj/16.17.5353 . 0261-4189 .
24. Lebrun JJ, Takabe K, Chen Y, Vale W . Roles of pathway-specific and inhibitory Smads in activin receptor signaling . Mol. Endocrinol. . 13 . 1 . 15–23 . January 1999 . 9892009 . 10.1210/mend.13.1.0218 . 26825706 . 0888-8809 . free .
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27. Leong GM, Subramaniam N, Figueroa J, Flanagan JL, Hayman MJ, Eisman JA, Kouzmenko AP . Ski-interacting protein interacts with Smad proteins to augment transforming growth factor-beta-dependent transcription . J. Biol. Chem. . 276 . 21 . 18243–8 . May 2001 . 11278756 . 10.1074/jbc.M010815200 . 0021-9258 . free .
28. Datta PK, Moses HL . STRAP and Smad7 Synergize in the Inhibition of Transforming Growth Factor β Signaling . Mol. Cell. Biol. . 20 . 9 . 3157–67 . May 2000 . 10757800 . 85610 . 10.1128/MCB.20.9.3157-3167.2000 . 0270-7306 .