Mothers against decapentaplegic homolog 2

SMAD2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1DEV, 1KHX, 1U7V, 2LB3
Identifiers
Aliases	SMAD2 , JV18, JV18-1, MADH2, MADR2, hMAD-2, hSMAD family member 2, LDS6, CHTD8
External IDs	OMIM: 601366 MGI: 108051 HomoloGene: 21197 GeneCards: SMAD2
Gene location (Human) Chr. Chromosome 18 (human) [1] Band 18q21.1 Start 47,808,957 bp [1] End 47,931,146 bp [1]
Gene location (Mouse) Chr. Chromosome 18 (mouse) [2] Band 18 E3|18 51.42 cM Start 76,374,651 bp [2] End 76,444,034 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon sperm secondary oocyte germinal epithelium monocyte islet of Langerhans amniotic fluid hair follicle endothelial cell sural nerve Top expressed in saccule otic placode secondary oocyte endocardial cushion trigeminal ganglion ganglionic eminence nerve fiber layer sciatic nerve atrioventricular valve hand More reference expression data BioGPS More reference expression data
Gene ontology Molecular function phosphatase binding I-SMAD binding DNA-binding transcription factor activity DNA-binding transcription activator activity, RNA polymerase II-specific R-SMAD binding co-SMAD binding transcription factor binding metal ion binding RNA polymerase II cis-regulatory region sequence-specific DNA binding transforming growth factor beta receptor binding type I transforming growth factor beta receptor binding protein homodimerization activity chromatin binding protein binding double-stranded DNA binding SMAD binding DNA binding protein heterodimerization activity ubiquitin protein ligase binding primary miRNA binding disordered domain specific binding DNA-binding transcription factor activity, RNA polymerase II-specific tau protein binding Cellular component cytoplasm cytosol nucleus heteromeric SMAD protein complex SMAD protein complex transcription regulator complex intracellular anatomical structure nucleoplasm activin responsive factor complex protein-containing complex Biological process pattern specification process ureteric bud development endoderm development response to cholesterol organ growth embryonic pattern specification zygotic specification of dorsal/ventral axis post-embryonic development protein phosphorylation pericardium development regulation of binding transforming growth factor beta receptor signaling pathway negative regulation of cell population proliferation cell fate commitment common-partner SMAD protein phosphorylation regulation of transcription, DNA-templated SMAD protein signal transduction lung development signal transduction involved in regulation of gene expression insulin secretion in utero embryonic development negative regulation of transforming growth factor beta receptor signaling pathway negative regulation of gene expression nodal signaling pathway positive regulation of transcription, DNA-templated heart development pancreas development endoderm formation activin receptor signaling pathway SMAD protein complex assembly positive regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry embryonic foregut morphogenesis negative regulation of transcription by RNA polymerase II response to glucose positive regulation of epithelial to mesenchymal transition developmental growth gastrulation primary miRNA processing positive regulation of BMP signaling pathway embryonic cranial skeleton morphogenesis negative regulation of transcription, DNA-templated paraxial mesoderm morphogenesis intracellular signal transduction somatic stem cell population maintenance mesoderm formation regulation of transforming growth factor beta receptor signaling pathway positive regulation of gene expression anterior/posterior pattern specification positive regulation of transcription by RNA polymerase II transcription, DNA-templated transcription by RNA polymerase II protein deubiquitination wound healing adrenal gland development secondary palate development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4087 17126 Ensembl ENSG00000175387 ENSMUSG00000024563 UniProt Q15796 Q62432 RefSeq (mRNA) NM_001003652 NM_001135937 NM_005901 NM_001252481 NM_010754 NM_001311070 RefSeq (protein) NP_001003652 NP_001129409 NP_005892 NP_001239410 NP_001297999 NP_034884 Location (UCSC) Chr 18: 47.81 – 47.93 Mb Chr 18: 76.37 – 76.44 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. ^{[5] [6]} 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. ^[7]

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. ^[8]

Interactions

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

• ANAPC10, ^[9]
• DAB2, ^[10]
• EP300, ^{[11] [12]}
• FOXH1, ^{[11] [13] [14] [15] [16]}
• HDAC1, ^[11]
• TGIF1, ^{[11] [12]}
• Insulin receptor, ^[17]
• LEF1, ^[18]
• Myc, ^[19]
• MEF2A, ^[20]
• PIAS3, ^[21]
• PIN1, ^[22]
• SKI protein, ^{[23] [24]}
• SKIL, ^{[25] [26]}
• SMAD3, ^{[27] [28]}
• SMURF2, ^{[22] [29] [30]}
• SNW1, ^[31]
• STRAP ^[32]
• WWTR1

References

1. GRCh38: Ensembl release 89: ENSG00000175387 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024563 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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. S2CID   531842.
6. 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. S2CID   10124489.
7. "Entrez Gene: SMAD2 SMAD family member 2".
8. "Sonic Hedgehog, DICER, and the Problem With Naming Genes", Sep 26, 2014, Michael White. psmag.com
9. 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.
10. 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.
11. 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. S2CID   6907878.
12. 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. Bibcode:2001PNAS...98.6198P. doi: 10.1073/pnas.101579798 . ISSN   0027-8424. PMC   33445 . PMID   11371641.
13. 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. doi:10.1128/MCB.19.1.424. ISSN   0270-7306. PMC   83900 . PMID   9858566.
14. 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.
15. 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.
16. 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. Bibcode:1997Natur.389...85C. doi:10.1038/38008. ISSN   0028-0836. PMID   9288972. S2CID   11927346.
17. 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.
18. 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. Bibcode:2000PNAS...97.8358L. doi: 10.1073/pnas.150152697 . ISSN   0027-8424. PMC   26952 . PMID   10890911.
19. 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.
20. 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.
21. 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. Bibcode:2004PNAS..101...99L. doi: 10.1073/pnas.0307598100 . ISSN   0027-8424. PMC   314145 . PMID   14691252.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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. S2CID   26825706.
29. 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.
30. 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. S2CID   23270947.
31. 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.
32. 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. S2CID   84458561.
• 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.