smad proteins


Summary: A family of proteins that are involved in the translocation of signals from TGF-BETA RECEPTORS; BONE MORPHOGENETIC PROTEIN RECEPTORS; and other surface receptors to the CELL NUCLEUS. They were originally identified as a class of proteins that are related to the mothers against decapentaplegic protein, Drosophila and sma proteins from CAENORHABDITIS ELEGANS.

Top Publications

  1. Lan H, Chung A. TGF-?/Smad signaling in kidney disease. Semin Nephrol. 2012;32:236-43 pubmed publisher
    ..Advances in understanding of the mechanisms of TGF-?/Smad signaling in renal fibrosis and inflammation during chronic kidney diseases should provide a better therapeutic strategy to combat kidney diseases. ..
  2. Sundqvist A, Zieba A, Vasilaki E, Herrera Hidalgo C, Soderberg O, Koinuma D, et al. Specific interactions between Smad proteins and AP-1 components determine TGF?-induced breast cancer cell invasion. Oncogene. 2013;32:3606-15 pubmed publisher
    ..Together these results suggest that in particular formation of Smad2/3-Fra1 complexes may reflect activation of the Smad/AP-1-dependent TGF?-induced invasion program. ..
  3. Sanvitale C, Kerr G, Chaikuad A, Ramel M, Mohedas A, Reichert S, et al. A new class of small molecule inhibitor of BMP signaling. PLoS ONE. 2013;8:e62721 pubmed publisher
    ..The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development. ..
  4. Yao Q, Xu B, Wang J, Liu H, Zhang S, Tu C. Inhibition by curcumin of multiple sites of the transforming growth factor-beta1 signalling pathway ameliorates the progression of liver fibrosis induced by carbon tetrachloride in rats. BMC Complement Altern Med. 2012;12:156 pubmed publisher
    ..These data suggest that curcumin might be an effective antifibrotic drug in the prevention of liver disease progression. ..
  5. Massague J. TGF? signalling in context. Nat Rev Mol Cell Biol. 2012;13:616-30 pubmed publisher
    ..However, an old mystery has endured: how does the context determine the cellular response to TGF?? Solving this question is key to understanding TGF? biology and its many malfunctions. Recent progress is pointing at answers. ..
  6. Huse K, Bakkebø M, Walchli S, Oksvold M, Hilden V, Forfang L, et al. Role of Smad proteins in resistance to BMP-induced growth inhibition in B-cell lymphoma. PLoS ONE. 2012;7:e46117 pubmed publisher
    ..This work highlights the role of Smads in determining the sensitivity to BMPs and shows that upregulation of Smad7 in cancer cells is sufficient to escape the negative effects of BMPs. ..
  7. Wu H, Mezghenna K, Marmol P, Guo T, Moliner A, Yang S, et al. Differential regulation of mouse pancreatic islet insulin secretion and Smad proteins by activin ligands. Diabetologia. 2014;57:148-56 pubmed publisher
  8. Pommier R, Gout J, Vincent D, Cano C, Kaniewski B, Martel S, et al. The human NUPR1/P8 gene is transcriptionally activated by transforming growth factor ? via the SMAD signalling pathway. Biochem J. 2012;445:285-93 pubmed publisher
    ..We show that this activation is mediated by the SMAD proteins, which are transcription factors specifically involved in the signalling of TGF? superfamily members...
  9. Hisada K, Hata K, Ichida F, Matsubara T, Orimo H, Nakano T, et al. Retinoic acid regulates commitment of undifferentiated mesenchymal stem cells into osteoblasts and adipocytes. J Bone Miner Metab. 2013;31:53-63 pubmed publisher
    ..In conclusion, our data suggest that RA regulates commitment of MSCs into osteoblasts and adipocytes by controlling transcriptional regulators. ..

More Information


  1. Yu J, He X, Chen Y, Hao Y, Yang S, Wang L, et al. Myotubularin-related protein 4 (MTMR4) attenuates BMP/Dpp signaling by dephosphorylation of Smad proteins. J Biol Chem. 2013;288:79-88 pubmed publisher
    ..In conclusion, this study has suggested that MTMR4 is a necessary negative modulator for the homeostasis of BMP/Dpp signaling. ..
  2. Yumoto K, Thomas P, Lane J, Matsuzaki K, Inagaki M, Ninomiya Tsuji J, et al. TGF-?-activated kinase 1 (Tak1) mediates agonist-induced Smad activation and linker region phosphorylation in embryonic craniofacial neural crest-derived cells. J Biol Chem. 2013;288:13467-80 pubmed publisher
    ..The role of Smad-independent TGF-? signaling in craniofacial development is poorly elucidated...
  3. Park J, Lee C, Suh J, Chae J, Moon K. Nuclear expression of Smad proteins and its prognostic significance in clear cell renal cell carcinoma. Hum Pathol. 2013;44:2047-54 pubmed publisher
    ..These results suggest that nuclear expressions of Smad3 and Smad4 were related to prognosis of clear cell renal cell carcinoma patients and may serve as novel prognostic markers in clear cell renal cell carcinoma patients. ..
  4. Matsuzaki K. Smad phospho-isoforms direct context-dependent TGF-? signaling. Cytokine Growth Factor Rev. 2013;24:385-99 pubmed publisher
    ..b>Smad proteins, which convey signals from TGF-? receptors to the nucleus, possess intermediate linker regions connecting Mad ..
  5. Kaneko S, Chen X, Lu P, Yao X, Wright T, Rajurkar M, et al. Smad inhibition by the Ste20 kinase Misshapen. Proc Natl Acad Sci U S A. 2011;108:11127-32 pubmed publisher
    ..Our findings thus reveal a function of Msn independent of its impact on MAP kinase cascades. This Smad inhibition mechanism by Msn likely has important implications for development and disease. ..
  6. Drabsch Y, Ten Dijke P. TGF-? signalling and its role in cancer progression and metastasis. Cancer Metastasis Rev. 2012;31:553-68 pubmed publisher
    ..Furthermore, several molecular targets with great potential in therapeutic interventions have been identified. This review discusses the TGF-? signalling pathway, its involvement in cancer and current therapeutic approaches. ..
  7. Lan H, Chung A. Transforming growth factor-? and Smads. Contrib Nephrol. 2011;170:75-82 pubmed publisher
    ..In conclusion, TGF-?/Smad signaling plays a critical role in DN. A better understanding of the role of TGF-?/Smad signaling in the development of DN should provide an effective therapeutic strategy to combat DN. ..
  8. Meyer C, Godoy P, Bachmann A, Liu Y, Barzan D, Ilkavets I, et al. Distinct role of endocytosis for Smad and non-Smad TGF-? signaling regulation in hepatocytes. J Hepatol. 2011;55:369-78 pubmed publisher
    ..Endocytosis is critical for TGF-? signaling regulation in hepatocytes and determines gene expression signature and (patho)physiological outcome. ..
  9. Han L, Gotlieb A. Fibroblast growth factor-2 promotes in vitro mitral valve interstitial cell repair through transforming growth factor-?/Smad signaling. Am J Pathol. 2011;178:119-27 pubmed publisher
    ..Fibroblast growth factor-2 promotes in vitro VIC wound repair, at least in part, through the TGF-?/Smad2/3 signaling pathway. ..
  10. Kim S, Yoon S, Chuong E, Oyolu C, Wills A, Gupta R, et al. Chromatin and transcriptional signatures for Nodal signaling during endoderm formation in hESCs. Dev Biol. 2011;357:492-504 pubmed publisher
    ..The correlation between SMAD2/3 binding, monovalent formation and transcriptional activation suggests a mechanism by which SMAD proteins coordinate with chromatin at critical promoters to drive endoderm specification.
  11. Xi Q, Wang Z, Zaromytidou A, Zhang X, Chow Tsang L, Liu J, et al. A poised chromatin platform for TGF-? access to master regulators. Cell. 2011;147:1511-24 pubmed publisher
    ..In turn, Smad4 increases K18 acetylation to augment TRIM33-Smad2/3 binding. Thus, nodal effectors use the H3K9me3 mark as a platform to switch master regulators of stem cell differentiation from the poised to the active state. ..
  12. Ka S, Yeh Y, Huang X, Chao T, Hung Y, Yu C, et al. Kidney-targeting Smad7 gene transfer inhibits renal TGF-?/MAD homologue (SMAD) and nuclear factor ?B (NF-?B) signalling pathways, and improves diabetic nephropathy in mice. Diabetologia. 2012;55:509-19 pubmed publisher
    ..Our results clearly demonstrate that kidney-targeting Smad7 gene transfer may be an effective therapy for type 2 diabetic nephropathy, acting via simultaneous modulation of the TGF-?/SMAD and NF-?B signalling pathways. ..
  13. PERRON J, Dodd J. Inductive specification and axonal orientation of spinal neurons mediated by divergent bone morphogenetic protein signaling pathways. Neural Dev. 2011;6:36 pubmed publisher
    ..A model is proposed whereby selective engagement of BMP receptor subunits underlies choice of signaling pathway. ..
  14. Mohammad K, Javelaud D, Fournier P, Niewolna M, McKenna C, Peng X, et al. TGF-beta-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases. Cancer Res. 2011;71:175-84 pubmed publisher
    ..Our results demonstrate that therapeutic targeting of TGF-? may prevent the development of melanoma bone metastases and decrease the progression of established osteolytic lesions. ..
  15. Al Salihi M, Herhaus L, Sapkota G. Regulation of the transforming growth factor ? pathway by reversible ubiquitylation. Open Biol. 2012;2:120082 pubmed publisher
    ..In this report, we provide an overview of current understanding of the regulation of TGF? signalling by E3 ubiquitin ligases and deubiquitylases. ..
  16. Zi Z, Chapnick D, Liu X. Dynamics of TGF-?/Smad signaling. FEBS Lett. 2012;586:1921-8 pubmed publisher
    ..These studies reveal many interesting dynamics of TGF-? signaling and how cells quantitatively decode variable doses of TGF-? stimulation. ..
  17. Cai J, Pardali E, Sanchez Duffhues G, Ten Dijke P. BMP signaling in vascular diseases. FEBS Lett. 2012;586:1993-2002 pubmed publisher
    ..In this review we discuss the role of BMP signaling in vascular diseases and the value of BMP signaling as a vascular disease marker or a therapeutic target. ..
  18. Handra Luca A, Hammel P, Sauvanet A, Ruszniewski P, Couvelard A. Tumoral epithelial and stromal expression of SMAD proteins in pancreatic ductal adenocarcinomas. J Hepatobiliary Pancreat Sci. 2013;20:294-302 pubmed publisher
    b>SMAD proteins, intracellular mediators of the transforming growth factor (TGF)-beta pathway, function within two axes, the SMAD1/5/8 and SMAD2/3, connected to TGF-beta and bone morphogenetic protein (BMP) ligands...
  19. Ueberham U, Hilbrich I, Ueberham E, Rohn S, Glöckner P, Dietrich K, et al. Transcriptional control of cell cycle-dependent kinase 4 by Smad proteins--implications for Alzheimer's disease. Neurobiol Aging. 2012;33:2827-40 pubmed publisher
    ..During brain development, neuronal differentiation is regulated by Smad proteins, which are elements of the canonical transforming growth factor ? (TGF-?) signaling pathway, linking receptor ..
  20. Oh C, Kim J, Min A, Park K, Harris R, Kim H, et al. Sulforaphane attenuates hepatic fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-?/Smad signaling. Free Radic Biol Med. 2012;52:671-682 pubmed publisher
    ..Collectively, these results show that SFN elicits an antifibrotic effect on hepatic fibrosis through Nrf2-mediated inhibition of the TGF-?/Smad signaling and subsequent suppression of HSC activation and fibrogenic gene expression. ..
  21. Buschke S, Stark H, Cerezo A, Prätzel Wunder S, Boehnke K, Kollar J, et al. A decisive function of transforming growth factor-?/Smad signaling in tissue morphogenesis and differentiation of human HaCaT keratinocytes. Mol Biol Cell. 2011;22:782-94 pubmed publisher
  22. Davis Dusenbery B, Hata A. Smad-mediated miRNA processing: a critical role for a conserved RNA sequence. RNA Biol. 2011;8:71-6 pubmed
    ..In this review we discuss the role of the Smads in the regulation of miRNA processing in response to Transforming Growth Factor-? stimulation. ..
  23. Sovershaev M, Egorina E, Sovershaev T, Svensson B, Hansen J. Increased expression of TF in BMP-7-treated human mononuclear cells depends on activation of select MAPK signaling pathways. Thromb Res. 2011;128:e154-9 pubmed publisher
    ..BMP-7-dependent activation of TF in human MNCs by BMP-7 is accompanied by activation of canonic Smad1/5/8 signaling pathway and depends on activation of Erk1/2 and p38. ..
  24. Matsuzaki K. Smad phosphoisoform signaling specificity: the right place at the right time. Carcinogenesis. 2011;32:1578-88 pubmed publisher
    ..b>Smad proteins, which convey signals from TGF-? receptors to the nucleus, have intermediate linker regions between conserved ..
  25. Holien T, Våtsveen T, Hella H, Rampa C, Brede G, Grøseth L, et al. Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC. Leukemia. 2012;26:1073-80 pubmed publisher
    ..We also found that myeloma cells harboring immunoglobulin (IG)-MYC translocations evaded BMP-induced apoptosis, suggesting a novel way for myeloma cells to overcome potential tumor suppression by BMPs. ..
  26. Hagihara M, Endo M, Hata K, Higuchi C, Takaoka K, Yoshikawa H, et al. Neogenin, a receptor for bone morphogenetic proteins. J Biol Chem. 2011;286:5157-65 pubmed publisher
    ..Taken together, our findings suggest that neogenin negatively regulates the functions of BMP and that this effect of neogenin is mediated by the activation of RhoA. ..
  27. Chen M, Lv Z, Jiang S. The effects of triptolide on airway remodelling and transforming growth factor-??/Smad signalling pathway in ovalbumin-sensitized mice. Immunology. 2011;132:376-84 pubmed publisher
    ..Triptolide may function as an inhibitor of asthma airway remodelling. It may be a potential drug for the treatment of patients with a severe asthma airway. ..
  28. Javelaud D, Alexaki V, Dennler S, Mohammad K, Guise T, Mauviel A. TGF-?/SMAD/GLI2 signaling axis in cancer progression and metastasis. Cancer Res. 2011;71:5606-10 pubmed publisher
    ..This short review summarizes recent knowledge about GLI2 function and mechanisms of action downstream of TGF-? in cancer. ..
  29. Sun Y, Hu J, Zhou L, Pollard S, Smith A. Interplay between FGF2 and BMP controls the self-renewal, dormancy and differentiation of rat neural stem cells. J Cell Sci. 2011;124:1867-77 pubmed publisher
  30. Santibanez J, Quintanilla M, Bernabeu C. TGF-?/TGF-? receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 2011;121:233-51 pubmed publisher
  31. Mu Y, Gudey S, Landström M. Non-Smad signaling pathways. Cell Tissue Res. 2012;347:11-20 pubmed publisher
    ..In this review, we discuss recent findings in the field of TGF?-induced responses by non-Smad signaling pathways. ..
  32. Bidart M, Ricard N, Levet S, Samson M, Mallet C, David L, et al. BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain. Cell Mol Life Sci. 2012;69:313-24 pubmed publisher
    ..Taken together, our results argue for the role of BMP9 as a hepatocyte-derived factor, circulating in inactive (40%) and active (60%) forms, the latter constantly activating endothelial cells to maintain them in a resting state. ..
  33. Maegdefrau U, Bosserhoff A. BMP activated Smad signaling strongly promotes migration and invasion of hepatocellular carcinoma cells. Exp Mol Pathol. 2012;92:74-81 pubmed publisher
    ..In summary, our findings demonstrate enhanced expression levels of several BMPs in HCC supporting enhanced migratory and invasive phenotype of HCC cells mainly via activation of Smad signaling. ..
  34. Kim D, Kwon E, Hong G, Lee Y, Lee S, Ro J. Cigarette smoke exacerbates mouse allergic asthma through Smad proteins expressed in mast cells. Respir Res. 2011;12:49 pubmed publisher
    ..The data suggest that smoke exposure enhances antigen-induced mast cell activation via TGF-?/Smad signaling pathways in mouse allergic asthma, and that it exacerbates airway inflammation and remodeling. ..
  35. Fu G, Peng C. Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells. Oncogene. 2011;30:3953-66 pubmed publisher
    ..Furthermore, IP assays revealed that FoxO3a formed complexes with Smad proteins and that Nodal enhanced the binding of FoxO3a to the CCNG2 promoter...
  36. Choi K, Lee K, Ryu S, Im M, Kook K, Choi C. Pirfenidone inhibits transforming growth factor-?1-induced fibrogenesis by blocking nuclear translocation of Smads in human retinal pigment epithelial cell line ARPE-19. Mol Vis. 2012;18:1010-20 pubmed
    ..These results collectively provide a rational background for future evaluation of pirfenidone as a potential antifibrotic agent for treating proliferative vitreoretinopathy and other fibrotic retinal disorders. ..
  37. Susarla B, Laing E, Yu P, Katagiri Y, Geller H, Symes A. Smad proteins differentially regulate transforming growth factor-β-mediated induction of chondroitin sulfate proteoglycans. J Neurochem. 2011;119:868-78 pubmed publisher
    ..Our data implicate TGF-β Smad3-mediated induction of 4-sulfation as a critical determinant of the permissiveness of astrocyte secreted CSPGs for axonal growth. ..
  38. Patel N, Masaratana P, Diaz Castro J, Latunde Dada G, Qureshi A, Lockyer P, et al. BMPER protein is a negative regulator of hepcidin and is up-regulated in hypotransferrinemic mice. J Biol Chem. 2012;287:4099-106 pubmed publisher
    ..Thus Bmper may play an important role in suppressing hepcidin production in hypotransferrinemic mice. ..
  39. Kurooka H, Nakahiro T, Mori K, Sano K, Yokota Y. BMP signaling is responsible for serum-induced Id2 expression. Biochem Biophys Res Commun. 2012;420:281-7 pubmed publisher
    ..Mutation analysis demonstrated that the binding sites for Smad proteins in the Id2 BRE were critical for serum response of the 4.6-kb whole construct...
  40. Xu D, Zhao Y, Wang J, He J, Weng Y, Luo J. Smads, p38 and ERK1/2 are involved in BMP9-induced osteogenic differentiation of C3H10T1/2 mesenchymal stem cells. BMB Rep. 2012;45:247-52 pubmed
    ..Also, it is noteworthy that p38 and ERK1/2 may play opposing regulatory roles in mediating BMP9-induced osteogenic differentiation of C3H10T1/2 cells. ..
  41. Ikushima H, Miyazono K. TGF-? signal transduction spreading to a wider field: a broad variety of mechanisms for context-dependent effects of TGF-?. Cell Tissue Res. 2012;347:37-49 pubmed publisher
    ..The TGF-? ligand induces the receptors directly to phosphorylate and activate Smad proteins, which then form transcriptional complexes to control target genes...
  42. Agricola E, Randall R, Gaarenstroom T, Dupont S, Hill C. Recruitment of TIF1? to chromatin via its PHD finger-bromodomain activates its ubiquitin ligase and transcriptional repressor activities. Mol Cell. 2011;43:85-96 pubmed publisher
    ..We propose a model of TIF1? activity in which it dictates the residence time of activated Smad complexes at promoters of TGF-? superfamily target genes. ..
  43. Soond S, Chantry A. How ubiquitination regulates the TGF-? signalling pathway: new insights and new players: new isoforms of ubiquitin-activating enzymes in the E1-E3 families join the game. Bioessays. 2011;33:749-58 pubmed publisher
    ..Moreover, we now broaden these observations to incorporate a growing number of protein isoforms within the ubiquitin ligase superfamily as a whole, and discuss their relevance in defining a new 'iso-ubiquitinome'. ..
  44. Varelas X, Samavarchi Tehrani P, Narimatsu M, Weiss A, Cockburn K, Larsen B, et al. The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-?-SMAD pathway. Dev Cell. 2010;19:831-44 pubmed publisher
    ..Accordingly, disruption of the Crumbs complex enhances TGF-? signaling and predisposes cells to TGF-?-mediated epithelial-to-mesenchymal transitions. ..
  45. Brandl M, Seidler B, Haller F, Adamski J, Schmid R, Saur D, et al. IKK(?) controls canonical TGF(ß)-SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in panc1 cells. J Cell Sci. 2010;123:4231-9 pubmed publisher
    ..Taken together, these findings indicate that IKK? contributes to the tumor-promoting function of the TGF?-SMAD signaling pathway in particular cancers. ..
  46. Heldin C, Moustakas A. Role of Smads in TGF? signaling. Cell Tissue Res. 2012;347:21-36 pubmed publisher
    ..The Smad function has been shown to be perturbed in certain diseases such as cancer. ..
  47. Frazer D, Wilkins S, Darshan D, Badrick A, McLaren G, Anderson G. Stimulated erythropoiesis with secondary iron loading leads to a decrease in hepcidin despite an increase in bone morphogenetic protein 6 expression. Br J Haematol. 2012;157:615-26 pubmed publisher
    ..Similar results were seen in Hbb(th3/+) mice. Thus the erythroid signal probably affects some components of BMP/SMAD signalling, but also may exert some independent effects. ..
  48. 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
    When directed to the nucleus by TGF-? or BMP signals, Smad proteins undergo cyclin-dependent kinase 8/9 (CDK8/9) and glycogen synthase kinase-3 (GSK3) phosphorylations that mediate the binding of YAP and Pin1 for transcriptional action, ..
  49. Larrivee B, Prahst C, Gordon E, del Toro R, Mathivet T, Duarte A, et al. ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway. Dev Cell. 2012;22:489-500 pubmed publisher
    ..Taken together, these results uncover a direct link between ALK1 and Notch signaling during vascular morphogenesis that may be relevant to the pathogenesis of HHT vascular lesions. ..
  50. Conidi A, Cazzola S, Beets K, Coddens K, Collart C, Cornelis F, et al. Few Smad proteins and many Smad-interacting proteins yield multiple functions and action modes in TGF?/BMP signaling in vivo. Cytokine Growth Factor Rev. 2011;22:287-300 pubmed publisher the many ligands of the TGF? family strongly converges towards only five receptor-activated, intracellular Smad proteins, which fall into two classes i.e. Smad2/3 and Smad1/5/8, respectively...
  51. Lin S, Yu L, Yang J, Liu Z, Karia B, Bishop A, et al. Mutant p53 disrupts role of ShcA protein in balancing Smad protein-dependent and -independent signaling activity of transforming growth factor-? (TGF-?). J Biol Chem. 2011;286:44023-34 pubmed publisher
  52. 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
    ..Thus, our results identify ADP-ribosylation of Smad proteins by PARP-1 as a key step in controlling the strength and duration of Smad-mediated transcription.
  53. Glinka Y, Stoilova S, Mohammed N, Prud homme G. Neuropilin-1 exerts co-receptor function for TGF-beta-1 on the membrane of cancer cells and enhances responses to both latent and active TGF-beta. Carcinogenesis. 2011;32:613-21 pubmed publisher
    ..We also show that Nrp2 has activities similar to Nrp1. We conclude that Nrp1 is a co-receptor for TGF-?1 and augments responses to latent and active TGF-?. Since TGF-? promotes metastasis this is highly relevant to cancer biology. ..