Mothers against decapentaplegic homolog 3

SMAD family member 3
PDB rendering based on 1dev.
Available structures PDB 1MHD, 1MJS, 1MK2, 1OZJ, 1U7F
Identifiers
Symbols	SMAD3; DKFZp586N0721; DKFZp686J10186; HSPC193; HsT17436; JV15-2; MADH3; MGC60396
External IDs	OMIM: 603109 MGI: 1201674 HomoloGene: 55937 GeneCards: SMAD3 Gene
Gene Ontology Molecular function • RNA polymerase II activating transcription factor binding • double-stranded DNA binding • sequence-specific DNA binding transcription factor activity • sequence-specific DNA binding transcription factor activity • ligand-regulated transcription factor activity • transforming growth factor beta receptor binding • protein binding • collagen binding • beta-catenin binding • transcription factor binding • protein kinase binding • transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity • ubiquitin protein ligase binding • protein homodimerization activity • sequence-specific DNA binding • transcription regulatory region DNA binding • metal ion binding • co-SMAD binding • R-SMAD binding Cellular component • intracellular • nucleus • nuclear inner membrane • nucleoplasm • nucleoplasm • transcription factor complex • cytoplasm • cytosol • cytosol • plasma membrane • receptor complex Biological process • negative regulation of transcription from RNA polymerase II promoter • negative regulation of transcription from RNA polymerase II promoter • skeletal system development • ureteric bud development • response to hypoxia • in utero embryonic development • mesoderm formation • somitogenesis • release of cytochrome c from mitochondria • liver development • negative regulation of protein phosphorylation • heart looping • osteoblast development • immune system development • transcription, DNA-dependent • transport • induction of apoptosis • activation of caspase activity • immune response • cell cycle arrest • transforming growth factor beta receptor signaling pathway • transforming growth factor beta receptor signaling pathway • SMAD protein complex assembly • gastrulation • endoderm development • negative regulation of cell proliferation • activation of pro-apoptotic gene products • embryonic pattern specification • positive regulation of alkaline phosphatase activity • positive regulation of epithelial to mesenchymal transition • regulation of striated muscle tissue development • regulation of transforming growth factor beta receptor signaling pathway • evasion of host defenses by virus • negative regulation of cell growth • positive regulation of cell migration • positive regulation of bone mineralization • thyroid gland development • primary microRNA processing • positive regulation of interleukin-1 beta production • regulation of transforming growth factor-beta2 production • positive regulation of transforming growth factor-beta3 production • positive regulation of catenin import into nucleus • wound healing • T cell activation • negative regulation of protein catabolic process • positive regulation of transcription factor import into nucleus • negative regulation of apoptosis • cell-cell junction organization • negative regulation of osteoblast differentiation • positive regulation of transcription, DNA-dependent • negative regulation of mitotic cell cycle • positive regulation of transcription from RNA polymerase II promoter • positive regulation of transcription from RNA polymerase II promoter • paraxial mesoderm morphogenesis • developmental growth • embryonic foregut morphogenesis • embryonic cranial skeleton morphogenesis • regulation of epithelial cell proliferation • regulation of immune response • protein stabilization • positive regulation of positive chemotaxis • regulation of binding • positive regulation of stress fiber assembly • positive regulation of focal adhesion assembly • pericardium development • transdifferentiation • lens fiber cell differentiation • positive regulation of canonical Wnt receptor signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4088	17127
Ensembl	ENSG00000166949	ENSMUSG00000032402
UniProt	P84022	Q3V3E0
RefSeq (mRNA)	NM_001145102.1	NM_016769.4
RefSeq (protein)	NP_001138574.1	NP_058049.3
Location (UCSC)	Chr 15: 67.36 – 67.49 Mb	Chr 9: 63.49 – 63.61 Mb
PubMed search	[1]	[2]

Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.^[1][2] SMAD3 is a member of the SMAD family of proteins.

The human SMAD3 gene is located on chromosome 15. It is one of several human homologues of a gene that was originally discovered in the fruit fly Drosophila melanogaster.

SMAD3 gene

The human SMAD3 gene is composed of 9 exons over 129,339 base pairs.

In mice, mutation of SMAD3 has been linked to colorectal adenocarcinoma,^[3] increased systemic inflammation, and accelerated wound healing.^[4] There is no conclusive evidence of similar activity in humans, however. A 2002 study investigated possible links between SMAD3 mutation and cancer of the pancreas and parathyroid gland, but found no connection. Increased SMAD3 activity has, however, been implicated in the pathogenesis of scleroderma. Smad3 is also a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes. Smad3-knockout mice have diminished adiposity^[5], with improved glucose tolerance and insulin sensitivity. Despite their reduced physical activity arising from muscle atrophy^[6], these Smad3-knockout mice are resistant to high-fat-diet induced obesity.

The herpes simplex virus can downregulate SMAD3 using the Lat transcription factor, even while the virus is in a latent state.

A reference assembly of SMAD3 is available.

SMAD3 protein

SMAD3, or Mothers against decapentaplegic homolog 3, is a polypeptide that, as its name describes, is a homolog of the Drosophila protein "Mothers against decapentaplegic". It belongs to the SMAD family of proteins, which belong to the TGFβ superfamily of modulators. Like many other TGFβ family members, SMAD3 is involved in cell signalling. SMAD3 modulates signals of activin and TGFβ's. Binding of this protein with SMAD4 enables its transmigration into the nucleus where it forms complexes with other proteins and acts as a transcription factor. SMAD3 is a receptor-regulated SMAD (R-SMAD).

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 inspired by organizations formed by mothers to oppose social problems, such as Mothers Against Drunk Driving (MADD).

References

1. ^ "Entrez Gene: SMAD3 SMAD family member 3". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4088. 
2. ^ Zhang Y, Feng X, We R, Derynck R (September 1996). "Receptor-associated Mad homologues synergize as effectors of the TGF-beta response". Nature 383 (6596): 168–72. doi:10.1038/383168a0. PMID 8774881. 
3. ^ Zhu Y, Richardson JA, Parada LF, Graff JM (September 1998). "Smad3 mutant mice develop metastatic colorectal cancer". Cell 94 (6): 703–14. doi:10.1016/S0092-8674(00)81730-4. PMID 9753318. 
4. ^ Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, Anzano M, Greenwell-Wild T, Wahl SM, Deng C, Roberts AB (September 1999). "Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response". Nat. Cell Biol. 1 (5): 260–6. doi:10.1038/12971. PMID 10559937. 
5. ^ Tan et al. (February 2011). "Smad3 deficiency in mice protects against insulin resistance and obesity induced by a high-fat diet". Diabetes 60 (2): 464–476. doi:10.2337/db10-0801. PMID 21270259. http://diabetes.diabetesjournals.org/content/60/2/464.long. 
6. ^ Ge et al. (April 2011). "Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts". Cell Res.. doi:10.1038/cr.2011.72. PMID 21502976. http://www.nature.com/cr/journal/vaop/ncurrent/full/cr201172a.html. 

Further reading

• Li H, Liu JP (2008). "Mechanisms of action of TGF-beta in cancer: evidence for Smad3 as a repressor of the hTERT gene.". Ann. N. Y. Acad. Sci. 1114: 56–68. doi:10.1196/annals.1396.016. PMID 17934056. 
• Matsuzaki K (2006). "Smad3 phosphoisoform-mediated signaling during sporadic human colorectal carcinogenesis.". Histol. Histopathol. 21 (6): 645–62. PMID 16528675. 
• 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. 
• 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. 
• 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. 
• Massagué J (1998). "TGF-beta signal transduction.". Annu. Rev. Biochem. 67: 753–91. doi:10.1146/annurev.biochem.67.1.753. PMID 9759503. 
• Walker LC, Waddell N, Ten Haaf A, et al. (2008). "Use of expression data and the CGEMS genome-wide breast cancer association study to identify genes that may modify risk in BRCA1/2 mutation carriers.". Breast Cancer Research and Treatment 112 (2): 229–36. doi:10.1007/s10549-007-9848-5. PMID 18095154. 
• Lee KB, Jeon JH, Choi I, et al. (2008). "Clusterin, a novel modulator of TGF-beta signaling, is involved in Smad2/3 stability.". Biochem. Biophys. Res. Commun. 366 (4): 905–9. doi:10.1016/j.bbrc.2007.12.033. PMID 18082619. 
• Kim TD, Shin S, Janknecht R (2008). "Repression of Smad3 activity by histone demethylase SMCX/JARID1C.". Biochem. Biophys. Res. Commun. 366 (2): 563–7. doi:10.1016/j.bbrc.2007.12.013. PMID 18078810. 
• Zhao X, Nicholls JM, Chen YG (2008). "Severe acute respiratory syndrome-associated coronavirus nucleocapsid protein interacts with Smad3 and modulates transforming growth factor-beta signaling.". J. Biol. Chem. 283 (6): 3272–80. doi:10.1074/jbc.M708033200. PMID 18055455. 
• Li T, Chiang JY (2007). "A novel role of transforming growth factor beta1 in transcriptional repression of human cholesterol 7alpha-hydroxylase gene.". Gastroenterology 133 (5): 1660–9. doi:10.1053/j.gastro.2007.08.042. PMID 17920062. 
• Lu S, Lee J, Revelo M, et al. (2007). "Smad3 is overexpressed in advanced human prostate cancer and necessary for progressive growth of prostate cancer cells in nude mice.". Clin. Cancer Res. 13 (19): 5692–702. doi:10.1158/1078-0432.CCR-07-1078. PMID 17908958. 
• Kalo E, Buganim Y, Shapira KE, et al. (2007). "Mutant p53 attenuates the SMAD-dependent transforming growth factor beta1 (TGF-beta1) signaling pathway by repressing the expression of TGF-beta receptor type II.". Mol. Cell. Biol. 27 (23): 8228–42. doi:10.1128/MCB.00374-07. PMC 2169171. PMID 17875924. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2169171. 
• Weng HL, Ciuclan L, Liu Y, et al. (2007). "Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes.". Hepatology 46 (4): 1257–70. doi:10.1002/hep.21806. PMID 17657819. 
• Dennler S, André J, Alexaki I, et al. (2007). "Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo.". Cancer Res. 67 (14): 6981–6. doi:10.1158/0008-5472.CAN-07-0491. PMID 17638910. 
• Zhang M, Lee CH, Luo DD, et al. (2007). "Polarity of response to transforming growth factor-beta1 in proximal tubular epithelial cells is regulated by beta-catenin.". J. Biol. Chem. 282 (39): 28639–47. doi:10.1074/jbc.M700594200. PMID 17623674. 
• Martin MM, Buckenberger JA, Jiang J, et al. (2007). "TGF-beta1 stimulates human AT1 receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways.". Am. J. Physiol. Lung Cell Mol. Physiol. 293 (3): L790–9. doi:10.1152/ajplung.00099.2007. PMC 2413071. PMID 17601799. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2413071. 
• Dai F, Chang C, Lin X, et al. (2007). "Erbin inhibits transforming growth factor beta signaling through a novel Smad-interacting domain.". Mol. Cell. Biol. 27 (17): 6183–94. doi:10.1128/MCB.00132-07. PMC 1952163. PMID 17591701. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1952163. 
• Levy L, Howell M, Das D, et al. (2007). "Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation.". Mol. Cell. Biol. 27 (17): 6068–83. doi:10.1128/MCB.00664-07. PMC 1952153. PMID 17591695. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1952153.