Gene Symbol: Smad3
Description: SMAD family member 3
Alias: HSPC193, HsT17436, JV15-2, LDS1C, LDS3, MADH3, mothers against decapentaplegic homolog 3, MAD homolog 3, MAD, mothers against decapentaplegic homolog 3, SMA- and MAD-related protein 3, SMAD, mothers against DPP homolog 3, hMAD-3, hSMAD3, mad homolog JV15-2, mad protein homolog, mad3, mothers against DPP homolog 3
Species: human
Products:     Smad3

Top Publications

  1. Chou W, Prokova V, Shiraishi K, Valcourt U, Moustakas A, Hadzopoulou Cladaras M, et al. Mechanism of a transcriptional cross talk between transforming growth factor-beta-regulated Smad3 and Smad4 proteins and orphan nuclear receptor hepatocyte nuclear factor-4. Mol Biol Cell. 2003;14:1279-94 pubmed
    ..In the present study, we show that Smad3 and Smad4 but not Smad2 physically interact with HNF-4 via their Mad homology 1 domains both in vitro and in vivo...
  2. Soond S, Chantry A. Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGF? signalling and EMT. Oncogene. 2011;30:2451-62 pubmed publisher
    ..We show that WWP2-FL interacts exclusively with Smad2, Smad3 and Smad7 in the TGF? pathway...
  3. Yamagata H, Matsuzaki K, Mori S, Yoshida K, Tahashi Y, Furukawa F, et al. Acceleration of Smad2 and Smad3 phosphorylation via c-Jun NH(2)-terminal kinase during human colorectal carcinogenesis. Cancer Res. 2005;65:157-65 pubmed
    ..Using antibodies specific to each phosphorylation site, we herein showed that Smad2 and Smad3 were phosphorylated at COOH-terminal regions but not at linker regions in normal colorectal epithelial cells and ..
  4. Hua F, Zhou J, Liu J, Zhu C, Cui B, Lin H, et al. Glycogen synthase kinase-3beta negatively regulates TGF-beta1 and Angiotensin II-mediated cellular activity through interaction with Smad3. Eur J Pharmacol. 2010;644:17-23 pubmed publisher
    ..Here we report that GSK3beta physically and functionally interacts with Smad3. The interaction between GSK3beta and Smad3 may participate in the negative regulation of transforming growth ..
  5. Yu H, Konigshoff M, Jayachandran A, Handley D, Seeger W, Kaminski N, et al. Transgelin is a direct target of TGF-beta/Smad3-dependent epithelial cell migration in lung fibrosis. FASEB J. 2008;22:1778-89 pubmed publisher
    ..Here, we identified the transgelin (tagln) gene as a novel immediate target of TGF-beta/Smad3-dependent gene expression in ATII cells using a Smad3 chromatin immunoprecipitation (ChIP) screen...
  6. Thuault S, Tan E, Peinado H, Cano A, Heldin C, Moustakas A. HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J Biol Chem. 2008;283:33437-46 pubmed publisher
    ..The data propose that HMGA2 acts in a gene-specific manner to orchestrate the transcriptional network necessary for the EMT program. ..
  7. Lee J, Revelo M, Wang X, Lu S, Dong Z. Smad3 is overexpressed in advanced human prostate cancer and necessary for progressive growth of prostate cancer cells in nude mice. Clin Cancer Res. 2007;13:5692-702 pubmed
    The purpose of this study was to investigate the potential role of Smad3, a key mediator of transforming growth factor-beta signaling, in progression of prostate cancer...
  8. Matsuura I, Chiang K, Lai C, He D, Wang G, Ramkumar R, et al. Pin1 promotes transforming growth factor-beta-induced migration and invasion. J Biol Chem. 2010;285:1754-64 pubmed publisher
    ..We further show that the phosphorylated threonine 179-proline motif in the Smad3 linker region is the major binding site for Pin1...
  9. Kalo E, Buganim Y, Shapira K, Besserglick H, Goldfinger N, Weisz L, et al. 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. 2007;27:8228-42 pubmed
    ..These data provide important insights into the molecular mechanisms that underlie mutant p53 "gain of function" pertaining to the TGF-beta signaling pathway. ..

More Information


  1. Lönn P, van der Heide L, Dahl M, Hellman U, Heldin C, Moustakas A. PARP-1 attenuates Smad-mediated transcription. Mol Cell. 2010;40:521-32 pubmed publisher
    ..Activation of TGF-? receptors leads to phosphorylation of Smad2 and Smad3, which oligomerize with Smad4 and accumulate in the nucleus where they recognize gene regulatory regions and ..
  2. Dubrovska A, Kanamoto T, Lomnytska M, Heldin C, Volodko N, Souchelnytskyi S. TGFbeta1/Smad3 counteracts BRCA1-dependent repair of DNA damage. Oncogene. 2005;24:2289-97 pubmed
    ..Here we show that Smad3 which is a component of the TGFbeta signaling pathway, forms a complex with BRCA1 in vitro and in vivo...
  3. Aragón E, Goerner N, Zaromytidou A, Xi Q, Escobedo A, Massagué J, et al. A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev. 2011;25:1275-88 pubmed publisher
    ..Similarly, in the TGF-? pathway, Smad3 phosphorylation by CDK8/9 creates binding sites for Pin1 and GSK3, then adds sites to enhance Nedd4L binding...
  4. Kurisaki A, Kurisaki K, Kowanetz M, Sugino H, Yoneda Y, Heldin C, et al. The mechanism of nuclear export of Smad3 involves exportin 4 and Ran. Mol Cell Biol. 2006;26:1318-32 pubmed
    Transforming growth factor beta (TGF-beta) receptors phosphorylate Smad3 and induce its nuclear import so it can regulate gene transcription...
  5. Hua F, Mu R, Liu J, Xue J, Wang Z, Lin H, et al. TRB3 interacts with SMAD3 promoting tumor cell migration and invasion. J Cell Sci. 2011;124:3235-46 pubmed publisher
    ..Here, we report that TRB3 is a novel SMAD3-interacting protein...
  6. Lin X, Duan X, Liang Y, Su Y, Wrighton K, Long J, et al. PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell. 2006;125:915-28 pubmed
    ..This work demonstrates that PPM1A/PP2Calpha, through dephosphorylation of Smad2/3, plays a critical role in terminating TGFbeta signaling. ..
  7. van der Linde D, van de Laar I, Bertoli Avella A, Oldenburg R, Bekkers J, Mattace Raso F, et al. Aggressive cardiovascular phenotype of aneurysms-osteoarthritis syndrome caused by pathogenic SMAD3 variants. J Am Coll Cardiol. 2012;60:397-403 pubmed publisher
    ..AOS, caused by pathogenic SMAD3 variants, is a recently described autosomal dominant syndrome characterized by aneurysms and arterial tortuosity ..
  8. Wrighton K, Willis D, Long J, Liu F, Lin X, Feng X. Small C-terminal domain phosphatases dephosphorylate the regulatory linker regions of Smad2 and Smad3 to enhance transforming growth factor-beta signaling. J Biol Chem. 2006;281:38365-75 pubmed
    ..Taken together, this work identifies the first example of a Smad2/3 linker phosphatase(s) and reveals an important new substrate for SCPs. ..
  9. Gao S, Alarcon C, Sapkota G, Rahman S, Chen P, Goerner N, et al. Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signaling. Mol Cell. 2009;36:457-68 pubmed publisher
    TGF-beta induces phosphorylation of the transcription factors Smad2 and Smad3 at the C terminus as well as at an interdomain linker region...
  10. Samani N, Erdmann J, Hall A, Hengstenberg C, Mangino M, Mayer B, et al. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007;357:443-53 pubmed
    ..3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease. ..
  11. Walker L, Waddell N, Ten Haaf A, Grimmond S, Spurdle A. 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 Res Treat. 2008;112:229-36 pubmed
    ..Similar approaches may be used to identify genes and underlying genetic risk factors that interact with exogenous stimulants to cause or modify any disease, without a priori knowledge of the pathways involved. ..
  12. Coutts S, Childs A, Fulton N, Collins C, Bayne R, McNeilly A, et al. Activin signals via SMAD2/3 between germ and somatic cells in the human fetal ovary and regulates kit ligand expression. Dev Biol. 2008;314:189-99 pubmed publisher
    ..e. preceding and during primordial follicle formation. SMAD3 mRNA expression increased 1.9 fold (P=0.02)...
  13. Luciakova K, Kollarovic G, Barath P, Nelson B. Growth-dependent repression of human adenine nucleotide translocator-2 (ANT2) transcription: evidence for the participation of Smad and Sp family proteins in the NF1-dependent repressor complex. Biochem J. 2008;412:123-30 pubmed publisher
    ..These findings suggest a possible functional relationship between the NF1 and Smad proteins that has not been previously observed. ..
  14. Koinuma D, Tsutsumi S, Kamimura N, Taniguchi H, Miyazawa K, Sunamura M, et al. Chromatin immunoprecipitation on microarray analysis of Smad2/3 binding sites reveals roles of ETS1 and TFAP2A in transforming growth factor beta signaling. Mol Cell Biol. 2009;29:172-86 pubmed publisher
    The Smad2 and Smad3 (Smad2/3) proteins are principally involved in the transmission of transforming growth factor beta (TGF-beta) signaling from the plasma membrane to the nucleus...
  15. Li H, Sekine M, Seng S, Avraham S, Avraham H. BRCA1 interacts with Smad3 and regulates Smad3-mediated TGF-beta signaling during oxidative stress responses. PLoS ONE. 2009;4:e7091 pubmed publisher
    ..Further, WT-BRCA1, but not mutated BRCA1 increased the expression of Smad3 protein in a dose-dependent manner, while silencing of WT-BRCA1 by siRNA decreased Smad3 and Smad4 interaction ..
  16. Herhaus L, Al Salihi M, MacArtney T, Weidlich S, Sapkota G. OTUB1 enhances TGF? signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3. Nat Commun. 2013;4:2519 pubmed publisher
    ..Our findings uncover a signal-induced phosphorylation-dependent recruitment of OTUB1 to its target in the TGF? pathway. ..
  17. Petersen M, Pardali E, van der Horst G, Cheung H, van den Hoogen C, van der Pluijm G, et al. Smad2 and Smad3 have opposing roles in breast cancer bone metastasis by differentially affecting tumor angiogenesis. Oncogene. 2010;29:1351-61 pubmed publisher
    ..elicits these dichotomous functions and which roles the principle intracellular effector proteins Smad2 and Smad3 have therein, is unclear...
  18. Daly A, Vizan P, Hill C. Smad3 protein levels are modulated by Ras activity and during the cell cycle to dictate transforming growth factor-beta responses. J Biol Chem. 2010;285:6489-97 pubmed publisher
    ..b>Smad3 is a central component of the TGF-beta signaling pathway, and once activated, Smad3 forms complexes with Smad4 or ..
  19. Valdes A, Spector T, Tamm A, Kisand K, Doherty S, Dennison E, et al. Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum. 2010;62:2347-52 pubmed publisher
    Smad3 (or, MADH3) is a key intracellular messenger in the transforming growth factor beta signaling pathway. In mice, Smad3 deficiency accelerates growth plate chondrocyte maturation and leads to an osteoarthritis (OA)-like disease...
  20. Walker L, Fredericksen Z, Wang X, Tarrell R, Pankratz V, Lindor N, et al. Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers. Breast Cancer Res. 2010;12:R102 pubmed publisher
    ..77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = ..
  21. Regalado E, Guo D, Villamizar C, Avidan N, Gilchrist D, McGillivray B, et al. Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ Res. 2011;109:680-6 pubmed publisher
    ..A novel frame shift mutation, p. N218fs (c.652delA), was identified in the SMAD3 gene and segregated with the vascular diseases in this family with a logarithm of odds score of 2.52...
  22. van de Laar I, van der Linde D, Oei E, Bos P, Bessems J, Bierma Zeinstra S, et al. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet. 2012;49:47-57 pubmed publisher
    ..AOS is caused by mutations in the SMAD3 gene...
  23. Wischmeijer A, Van Laer L, Tortora G, Bolar N, Van Camp G, Fransen E, et al. Thoracic aortic aneurysm in infancy in aneurysms-osteoarthritis syndrome due to a novel SMAD3 mutation: further delineation of the phenotype. Am J Med Genet A. 2013;161A:1028-35 pubmed publisher
    Recently, mutations in the SMAD3 gene were found to cause a new autosomal dominant aneurysm condition similar to Loeys-Dietz syndrome (LDS), mostly with osteoarthritis, called aneurysms-osteoarthritis syndrome (AOS)...
  24. Guo X, Ramirez A, Waddell D, Li Z, Liu X, Wang X. Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling. Genes Dev. 2008;22:106-20 pubmed publisher
    ..of tissues and cells is mainly determined by the expression level and activity of the effector proteins Smad2 and Smad3. It is not fully understood how the baseline properties of Smad3 are regulated, although this molecule is in ..
  25. Middlebrook B, Eldin K, Li X, Shivasankaran S, Pangas S. Smad1-Smad5 ovarian conditional knockout mice develop a disease profile similar to the juvenile form of human granulosa cell tumors. Endocrinology. 2009;150:5208-17 pubmed publisher
    ..These data suggest that the SMAD family, possibly through disruption of SMAD1/5 or activation of SMAD2/3 may contribute to the pathogenesis of JGCT in humans...
  26. Edlin R, TSAI S, Yamanouchi D, Wang C, Liu B, Kent K. Characterization of primary and restenotic atherosclerotic plaque from the superficial femoral artery: Potential role of Smad3 in regulation of SMC proliferation. J Vasc Surg. 2009;49:1289-95 pubmed publisher primary and restenotic lesions of the superficial femoral artery and analyze the contribution of TGF-beta/Smad3 signaling to the pathophysiology of peripheral artery occlusive disease...
  27. Nakano A, Koinuma D, Miyazawa K, Uchida T, Saitoh M, Kawabata M, et al. Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins. J Biol Chem. 2009;284:6109-15 pubmed publisher
    ..Pin1 interacted with Smad2 and Smad3 but not Smad4; this interaction was enhanced by the phosphorylation of (S/T)P motifs in the Smad linker region...
  28. Alarcon C, Zaromytidou A, Xi Q, Gao S, Yu J, Fujisawa S, et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways. Cell. 2009;139:757-69 pubmed publisher
    ..Thus, nuclear CDK8/9 drive a cycle of Smad utilization and disposal that is an integral part of canonical BMP and TGF-beta pathways. ..
  29. Ku J, Park S, Yoon K, Shin Y, Kim K, Choi J, et al. Genetic alterations of the TGF-beta signaling pathway in colorectal cancer cell lines: a novel mutation in Smad3 associated with the inactivation of TGF-beta-induced transcriptional activation. Cancer Lett. 2007;247:283-92 pubmed
    ..DNA synthesis rates after treating TGF-beta and checked for genetic alterations in TGF-betaRII, TGF-betaRI, Smad2, Smad3, and Smad4 in 12 colorectal cancer cell lines...
  30. Descargues P, Sil A, Sano Y, Korchynskyi O, Han G, Owens P, et al. IKKalpha is a critical coregulator of a Smad4-independent TGFbeta-Smad2/3 signaling pathway that controls keratinocyte differentiation. Proc Natl Acad Sci U S A. 2008;105:2487-92 pubmed publisher
    ..Mad2, and Ovol1, through the association with TGFbeta-regulated Smad2/3 transcription factors and is required for Smad3 recruitment to at least one of these targets...
  31. Zhang M, Wang M, Tan X, Li T, Zhang Y, Chen D. Smad3 prevents beta-catenin degradation and facilitates beta-catenin nuclear translocation in chondrocytes. J Biol Chem. 2010;285:8703-10 pubmed publisher
    Our previous study demonstrated that transforming growth factor (TGF)-beta activates beta-catenin signaling through Smad3 interaction with beta-catenin in chondrocytes...
  32. van de Laar I, Oldenburg R, Pals G, Roos Hesselink J, de Graaf B, Verhagen J, et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011;43:121-6 pubmed publisher
    ..We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-? pathway that is essential for TGF-? signal transmission...
  33. Tang L, Yamashita M, Coussens N, Tang Y, Wang X, Li C, et al. Ablation of Smurf2 reveals an inhibition in TGF-β signalling through multiple mono-ubiquitination of Smad3. EMBO J. 2011;30:4777-89 pubmed publisher
    ..poly-ubiquitination and degradation, we show that Smurf2 actually induces multiple mono-ubiquitination of Smad3 in vivo...
  34. Hilhorst Hofstee Y, Scholte A, Rijlaarsdam M, van Haeringen A, Kroft L, Reijnierse M, et al. An unanticipated copy number variant of chromosome 15 disrupting SMAD3 reveals a three-generation family at serious risk for aortic dissection. Clin Genet. 2013;83:337-44 pubmed publisher
    ..appearance of thoracic aortic aneurysms and dissections (FTAAD) have been characterized recently, one of which is SMAD3. Mutations of SMAD3 cause a new syndromic form of aortic aneurysms and dissections associated with skeletal ..
  35. Liying J, Yuchun T, Youcheng W, Yingchen W, Chunyu J, Yanling Y, et al. A SMAD3 gene polymorphism is related with osteoarthritis in a Northeast Chinese population. Rheumatol Int. 2013;33:1763-8 pubmed publisher
    Variants in the SMAD family member 3 (SMAD3) have recently been reported to be associated with osteoarthritis (OA) in European populations. However, the results are contestable...
  36. Zhang M, Lee C, Luo D, Krupa A, Fraser D, Phillips A. Polarity of response to transforming growth factor-beta1 in proximal tubular epithelial cells is regulated by beta-catenin. J Biol Chem. 2007;282:28639-47 pubmed
    ..b>Smad3 signaling response to TGF-beta1 was assessed by activity of the Smad3-responsive reporter gene construct (SBE)(4)-..
  37. He W, Dorn D, Erdjument Bromage H, Tempst P, Moore M, Massague J. Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway. Cell. 2006;125:929-41 pubmed
    ..Thus, Smad2/3-TIF1gamma and Smad2/3-Smad4 function as complementary effector arms in the control of hematopoietic cell fate by the TGFbeta/Smad pathway. ..
  38. Heikkinen P, Nummela M, Leivonen S, Westermarck J, Hill C, Kahari V, et al. Hypoxia-activated Smad3-specific dephosphorylation by PP2A. J Biol Chem. 2010;285:3740-9 pubmed publisher
    ..Here we show that upon hypoxia, the TGF-beta-induced phosphorylation of Smad3 was inhibited, although Smad2 remained phosphorylated...
  39. Pardali K, Kurisaki A, Moren A, ten Dijke P, Kardassis D, Moustakas A. Role of Smad proteins and transcription factor Sp1 in p21(Waf1/Cip1) regulation by transforming growth factor-beta. J Biol Chem. 2000;275:29244-56 pubmed
    ..Previously we have reported that the intracellular effectors of TGF-beta, Smad3 and Smad4, functionally cooperate with Sp1 to activate the human p21 promoter in hepatoma HepG2 cells...
  40. Li C, Zhu N, Tan R, Ballard P, Derynck R, Minoo P. Transforming growth factor-beta inhibits pulmonary surfactant protein B gene transcription through SMAD3 interactions with NKX2.1 and HNF-3 transcription factors. J Biol Chem. 2002;277:38399-408 pubmed
    ..Dominant negative mutants of Smads blocked the repressor activity of TGF-beta. SMAD3, but not SMAD2, mediated the repressor activity of TGF-beta on the Sp-B promoter...
  41. Leivonen S, Chantry A, Hakkinen L, Han J, Kahari V. Smad3 mediates transforming growth factor-beta-induced collagenase-3 (matrix metalloproteinase-13) expression in human gingival fibroblasts. Evidence for cross-talk between Smad3 and p38 signaling pathways. J Biol Chem. 2002;277:46338-46 pubmed
    ..Here, we have constructed recombinant adenoviruses harboring genes for hemagglutinin-tagged Smad2, Smad3, and Smad4 and used these in dissecting the role of Smads, the signaling mediators of TGF-beta, in regulation of ..
  42. Wang G, Long J, Matsuura I, He D, Liu F. The Smad3 linker region contains a transcriptional activation domain. Biochem J. 2005;386:29-34 pubmed
    ..b>Smad3 plays a key role in TGF-beta/Smad-mediated transcriptional responses...
  43. Massague J. TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753-91 pubmed
    ..Mutations in these pathways are the cause of various forms of human cancer and developmental disorders. ..
  44. Lo R, Massague J. Ubiquitin-dependent degradation of TGF-beta-activated smad2. Nat Cell Biol. 1999;1:472-8 pubmed
    ..If degradation is averted, the phosphorylated Smad2 remains in the nucleus in an active state. By targeting Smad2 for destruction, TGF-beta ensures the irreversible termination of its own signalling function. ..
  45. Mori S, Matsuzaki K, Yoshida K, Furukawa F, Tahashi Y, Yamagata H, et al. TGF-beta and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions. Oncogene. 2004;23:7416-29 pubmed
    ..and TGF-beta led to a potent increase in plasminogen activator inhibitor type 1 transcriptional activity through Smad3 phosphorylation at the linker region...
  46. Kamaraju A, Roberts A. Role of Rho/ROCK and p38 MAP kinase pathways in transforming growth factor-beta-mediated Smad-dependent growth inhibition of human breast carcinoma cells in vivo. J Biol Chem. 2005;280:1024-36 pubmed
    ..cancer cell line MCF10CA1h and demonstrate that p38 MAP kinase and Rho/ROCK pathways together with Smad2 and Smad3 are necessary for TGF-beta-mediated growth inhibition of this cell line...
  47. Furumatsu T, Tsuda M, Taniguchi N, Tajima Y, Asahara H. Smad3 induces chondrogenesis through the activation of SOX9 via CREB-binding protein/p300 recruitment. J Biol Chem. 2005;280:8343-50 pubmed
    ..Overexpressed Smad3 strongly induced the primary chondrogenesis of human mesenchymal stem cells...
  48. Qin B, Lam S, Correia J, Lin K. Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control. Genes Dev. 2002;16:1950-63 pubmed
    b>Smad3 transduces the signals of TGF-betas, coupling transmembrane receptor kinase activation to transcriptional control...
  49. Burton T, Liang B, Dibrov A, Amara F. Transforming growth factor-beta-induced transcription of the Alzheimer beta-amyloid precursor protein gene involves interaction between the CTCF-complex and Smads. Biochem Biophys Res Commun. 2002;295:713-23 pubmed
    ..These results demonstrate that TGF-beta activation of Smad protein complexes promotes transcription of the APP gene. Increased synthesis of APP may in part determine Abeta production and deposition in affected AD brain. ..
  50. Feng X, Liang Y, 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. 2002;9:133-43 pubmed
    ..In this study, we reveal that c-Myc physically interacts with Smad2 and Smad3, two specific signal transducers involved in TGF-beta signaling...
  51. Fukuchi M, Imamura T, Chiba T, Ebisawa T, Kawabata M, Tanaka K, et al. Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins. Mol Biol Cell. 2001;12:1431-43 pubmed
    ..Upon phosphorylation by the TGF-beta receptors, Smad3 translocates into the nucleus, recruits transcriptional coactivators and corepressors, and regulates transcription ..
  52. Liu X, Elia A, Law S, Golemis E, Farley J, Wang T. A novel ability of Smad3 to regulate proteasomal degradation of a Cas family member HEF1. EMBO J. 2000;19:6759-69 pubmed
    b>Smad3 is a key signal transducer of transforming growth factor-ss (TGF-ss) and activin, and is known to be a DNA-binding transcriptional regulator...
  53. Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, et al. TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J. 1997;16:5353-62 pubmed
    ..Smad2 and Smad3 are structurally highly similar and mediate TGF-beta signals...
  54. Zhang Y, Feng X, Derynck R. Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription. Nature. 1998;394:909-13 pubmed
    ..Here we show that Smad3 interacts directly with the TRE and that Smad3 and Smad4 can activate TGF-beta-inducible transcription from the ..
  55. Kretzschmar M, Doody J, Timokhina I, Massague J. A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. Genes Dev. 1999;13:804-16 pubmed
    ..TGFbeta signaling in mammary and lung epithelial cells by negatively regulating the TGFbeta mediators Smad2 and Smad3. Oncogenically activated Ras inhibits the TGFbeta-induced nuclear accumulation of Smad2 and Smad3 and Smad-..
  56. Liberati N, Datto M, Frederick J, Shen X, Wong C, Rougier Chapman E, et al. Smads bind directly to the Jun family of AP-1 transcription factors. Proc Natl Acad Sci U S A. 1999;96:4844-9 pubmed
    b>Smad3 and Smad4 are sequence-specific DNA-binding factors that bind to their consensus DNA-binding sites in response to transforming growth factor beta (TGFbeta) and activate transcription...
  57. Komuro A, Imamura T, Saitoh M, Yoshida Y, Yamori T, Miyazono K, et al. Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1). Oncogene. 2004;23:6914-23 pubmed
    ..Importantly, WWP1 and Smurfs were expressed in distinct patterns in human tissues and carcinoma cell lines, suggesting unique pathophysiological roles of WWP1 and Smurfs. ..
  58. Wicks S, Lui S, Abdel Wahab N, Mason R, Chantry A. Inactivation of smad-transforming growth factor beta signaling by Ca(2+)-calmodulin-dependent protein kinase II. Mol Cell Biol. 2000;20:8103-11 pubmed
    ..Cam kinase II induces in vivo phosphorylation of Smad2 and Smad4 and, to a lesser extent, Smad3. A phosphopeptide antiserum raised against Smad2 phosphoserine-240 reacted with Smad2 in vivo when coexpressed ..
  59. Koinuma D, Shinozaki M, Komuro A, Goto K, Saitoh M, Hanyu A, et al. Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7. EMBO J. 2003;22:6458-70 pubmed
    ..Arkadia may thus play an important role as an amplifier of TGF-beta superfamily signalling under both physiological and pathological conditions. ..
  60. Han S, Kim H, Seong D, Kim Y, Park Y, Bang Y, et al. Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer. Oncogene. 2004;23:1333-41 pubmed
    ..encoding TGF-beta receptors and Smads have been found genetically altered in certain human cancers, no mutation in Smad3 has been observed. Therefore, suppression of Smad3 expression may mediate key oncogenic properties of TGF-beta...
  61. Costamagna E, Garcia B, Santisteban P. The functional interaction between the paired domain transcription factor Pax8 and Smad3 is involved in transforming growth factor-beta repression of the sodium/iodide symporter gene. J Biol Chem. 2004;279:3439-46 pubmed
    ..inhibitory effect of TGF-beta was partially overcome by inhibitory Smad7 and mimicked by overexpression of either Smad3 or a constitutively activated mutant of TGF-beta receptor I (acALK-5)...
  62. Preobrazhenska O, Yakymovych M, Kanamoto T, Yakymovych I, Stoika R, Heldin C, et al. BRCA2 and Smad3 synergize in regulation of gene transcription. Oncogene. 2002;21:5660-4 pubmed
    b>Smad3 is an essential component in the intracellular signaling of transforming growth factor-beta (TGFbeta), which is a potent inhibitor of tumor cell proliferation...
  63. Akiyoshi S, Inoue H, Hanai J, Kusanagi K, Nemoto N, Miyazono K, et al. c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads. J Biol Chem. 1999;274:35269-77 pubmed
    ..c-Ski is incorporated in the Smad DNA binding complex, interferes with the interaction of Smad3 with a transcriptional co-activator, p300, and in turn recruits HDAC...