smad3 protein


Summary: A receptor-regulated smad protein that undergoes PHOSPHORYLATION by ACTIVIN RECEPTORS, TYPE I. Activated Smad3 can bind directly to DNA, and it regulates TRANSFORMING GROWTH FACTOR BETA and ACTIVIN signaling.

Top Publications

  1. Berthet E, Chen C, Butcher K, Schneider R, Alliston T, Amirtharajah M. Smad3 binds Scleraxis and Mohawk and regulates tendon matrix organization. J Orthop Res. 2013;31:1475-83 pubmed publisher
    ..Together these results indicate a central role for Smad3 in normal tendon formation and in the maintenance of mature tendon. ..
  2. Samarakoon R, Overstreet J, Higgins P. TGF-? signaling in tissue fibrosis: redox controls, target genes and therapeutic opportunities. Cell Signal. 2013;25:264-8 pubmed publisher
    ..Targeting ROS and ROS-activated cellular events is likely to have therapeutic implications in the management of fibrotic disorders, particularly in the context of prolonged TGF-?1 signaling. ..
  3. Fang W, Jokar I, Zou A, Lambert D, Dendukuri P, Cheng N. CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK)-dependent mechanisms. J Biol Chem. 2012;287:36593-608 pubmed publisher
    ..With these studies, we characterize an important role for CCL2/CCR2 chemokine signaling in regulating the intrinsic relationships between breast cancer cell motility and survival with implications on the metastatic process. ..
  4. Allen J, Cooke M, Alliston T. ECM stiffness primes the TGF? pathway to promote chondrocyte differentiation. Mol Biol Cell. 2012;23:3731-42 pubmed
    ..This work reveals novel mechanisms by which cells integrate physical and biochemical cues to exert a coordinated response to their unique cellular microenvironment...
  5. Chen C, Thuillier D, Chin E, Alliston T. Chondrocyte-intrinsic Smad3 represses Runx2-inducible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis. Arthritis Rheum. 2012;64:3278-89 pubmed publisher
    ..Selective activation of TGF? signaling through Smad3, rather than p38, may help to restore the balance between matrix synthesis and proteolysis that is lost in osteoarthritis. ..
  6. Chen J, Chen J, Nagai K, Plieth D, Tan M, Lee T, et al. EGFR signaling promotes TGF?-dependent renal fibrosis. J Am Soc Nephrol. 2012;23:215-24 pubmed publisher
  7. Masszi A, Kapus A. Smaddening complexity: the role of Smad3 in epithelial-myofibroblast transition. Cells Tissues Organs. 2011;193:41-52 pubmed publisher
    ..We suggest that EMyT is composed of an early, mesenchymal, Smad3-promoted phase and a late, myogenic, Smad3-inhibitable phase. ..
  8. Sasseville M, Ritter L, Nguyen T, Liu F, Mottershead D, Russell D, et al. Growth differentiation factor 9 signaling requires ERK1/2 activity in mouse granulosa and cumulus cells. J Cell Sci. 2010;123:3166-76 pubmed publisher
  9. Zhang Y, Zhang J, Navrazhina K, Argaw A, Zameer A, Gurfein B, et al. TGFbeta1 induces Jagged1 expression in astrocytes via ALK5 and Smad3 and regulates the balance between oligodendrocyte progenitor proliferation and differentiation. Glia. 2010;58:964-74 pubmed publisher

More Information


  1. Itoh F, Itoh S, Adachi T, Ichikawa K, Matsumura Y, Takagi T, et al. Smad2/Smad3 in endothelium is indispensable for vascular stability via S1PR1 and N-cadherin expressions. Blood. 2012;119:5320-8 pubmed publisher
    ..These results indicated that Smad2/3 signaling in ECs is indispensable for maintenance of vascular integrity via the fine-tuning of N-cadherin, VE-cadherin, and S1PR1 expressions in the vasculature...
  2. Guo L, Chen Y, Wang T, An J, Wang C, Shen Y, et al. Ox-LDL-induced TGF-?1 production in human alveolar epithelial cells: involvement of the Ras/ERK/PLTP pathway. J Cell Physiol. 2012;227:3185-91 pubmed publisher
    ..Taken together, we provide evidences that induction of TGF-?1 production and Smad3 phosphorylation by Ox-LDL is mediated by Ras/ERK/PLTP pathway in human alveolar epithelial cells. ..
  3. Basu R, Hubchak S, Hayashida T, Runyan C, Schumacker P, Schnaper H. Interdependence of HIF-1? and TGF-?/Smad3 signaling in normoxic and hypoxic renal epithelial cell collagen expression. Am J Physiol Renal Physiol. 2011;300:F898-905 pubmed publisher
    ..Taken together, our data demonstrate cooperation in signaling between Smad3 and HIF-1? and suggest a new paradigm in which HIF-1? is necessary for normoxic, TGF-?1-stimulated renal cell fibrogenesis. ..
  4. Wang Y, Symes A. Smad3 deficiency reduces neurogenesis in adult mice. J Mol Neurosci. 2010;41:383-96 pubmed publisher
    ..Our results suggest that signaling through Smad3 is needed to maintain the rate of cell division of neuronal precursors in the adult brain and hence the amount of neurogenesis, without altering neuronal cell fate. ..
  5. Kaddatz K, Adhikary T, Finkernagel F, Meissner W, Müller Brüsselbach S, Muller R. Transcriptional profiling identifies functional interactions of TGF ? and PPAR ?/? signaling: synergistic induction of ANGPTL4 transcription. J Biol Chem. 2010;285:29469-79 pubmed publisher
    ..Although the PPAR-E is not regulated by TGF?, it interacts with SMAD3, ETS1, RUNX2, and AP-1 in vivo, providing a possible mechanistic explanation for the observed synergism. ..
  6. 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
  7. Yang F, Huang X, Chung A, Hou C, Lai K, Lan H. Essential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition. J Pathol. 2010;221:390-401 pubmed publisher
    ..Smad3, but not Smad2, may be a mediator of EMT, while Smad7 may play a protective role in EMT in response to Ang II. ..
  8. Ahn S, Cha J, Kim J, Kim D, Trang H, Kim Y, et al. Smad3 regulates E-cadherin via miRNA-200 pathway. Oncogene. 2012;31:3051-9 pubmed publisher
    ..This represents a novel link between Smad3 and posttranscriptional regulation by miRNAs in epithelial-mesenchymal transition in gastric cancer cells. ..
  9. Charbonney E, Speight P, Masszi A, Nakano H, Kapus A. ?-catenin and Smad3 regulate the activity and stability of myocardin-related transcription factor during epithelial-myofibroblast transition. Mol Biol Cell. 2011;22:4472-85 pubmed publisher
    ..Thus ?-catenin controls MRTF-dependent transcription and emerges as a critical regulator of an array of cytoskeletal genes, the "CArGome."..
  10. Kolosova I, Nethery D, Kern J. Role of Smad2/3 and p38 MAP kinase in TGF-?1-induced epithelial-mesenchymal transition of pulmonary epithelial cells. J Cell Physiol. 2011;226:1248-54 pubmed publisher
    ..Both Smad2/3 and p38 MAPK had a role in regulation of TGF-?1-induced collagen expression. Furthermore, these data demonstrate that Smads and p38 MAPK differentially regulate EMT-related changes in pulmonary epithelial cells. ..
  11. 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
    ..These results demonstrate that TRB3 acts as a novel SMAD3-interacting protein to participate in the positive regulation of TGF-?-SMAD-mediated cellular biological functions. ..
  12. Chae K, Kang M, Lee J, Ryu B, Lee M, Her N, et al. Opposite functions of HIF-? isoforms in VEGF induction by TGF-?1 under non-hypoxic conditions. Oncogene. 2011;30:1213-28 pubmed publisher
    ..This study thus suggests that autocrine TGF-?1 production may contribute to tumor angiogenesis via HIF-2? signaling under non-hypoxic conditions, providing a selective growth advantage for prostate tumor cells. ..
  13. 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
    ..Our findings endorse the TGF-? pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis. ..
  14. Gong K, Xing D, Li P, Hilgers R, Hage F, Oparil S, et al. cGMP inhibits TGF-beta signaling by sequestering Smad3 with cytosolic beta2-tubulin in pulmonary artery smooth muscle cells. Mol Endocrinol. 2011;25:1794-803 pubmed publisher
  15. Long X, Miano J. Transforming growth factor-beta1 (TGF-beta1) utilizes distinct pathways for the transcriptional activation of microRNA 143/145 in human coronary artery smooth muscle cells. J Biol Chem. 2011;286:30119-29 pubmed publisher
    ..These results demonstrate a dual pathway for TGF-?1-induced transcription of miR143/145, thus revealing a novel mechanism underlying TGF-?1-induced human vascular SMC differentiation. ..
  16. Loughlin J. Genetics of osteoarthritis. Curr Opin Rheumatol. 2011;23:479-83 pubmed publisher
    ..Hopefully, combining the current with the new will help our attempts to understand the cause of this complex, common arthritis. ..
  17. Buckley S, Medina C, Ehrhardt C. Differential susceptibility to epithelial-mesenchymal transition (EMT) of alveolar, bronchial and intestinal epithelial cells in vitro and the effect of angiotensin II receptor inhibition. Cell Tissue Res. 2010;342:39-51 pubmed publisher
    ..Furthermore, our investigations point to the beneficial effect of telmisartan in partial abrogation of alveolar EMT. ..
  18. Cho I, Kim Y, Han C, Kim E, Anderson R, Lee Y, et al. E-cadherin antagonizes transforming growth factor ?1 gene induction in hepatic stellate cells by inhibiting RhoA-dependent Smad3 phosphorylation. Hepatology. 2010;52:2053-64 pubmed publisher
  19. Xu L, Kitani A, Stuelten C, McGrady G, Fuss I, Strober W. Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I. Immunity. 2010;33:313-25 pubmed publisher
    ..Thus, control of accessibility and binding of pSmad3 provides a common framework for positive and negative regulation of TGF-β-induced Foxp3 transcription. ..
  20. Bruce D, MacArtney T, Yong W, Shou W, Sapkota G. Protein phosphatase 5 modulates SMAD3 function in the transforming growth factor-? pathway. Cell Signal. 2012;24:1999-2006 pubmed publisher
    ..Rather surprisingly, this enhancement is due to the increased levels of SMAD3 protein observed in PP5-null MEFs compared to the wild type...
  21. Meng X, Huang X, Chung A, Qin W, Shao X, Igarashi P, et al. Smad2 protects against TGF-beta/Smad3-mediated renal fibrosis. J Am Soc Nephrol. 2010;21:1477-87 pubmed publisher
    ..In conclusion, in contrast to Smad3, Smad2 protects against TGF-beta-mediated fibrosis by counteracting TGF-beta/Smad3 signaling. ..
  22. 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
    ..Mutations are found in families with TAAD alone, along with families with TAAD, intracranial aneurysms, abdominal aortic and bilateral iliac aneurysms segregating in an autosomal dominant manner. ..
  23. Liu Z, Huang X, Lan H. Smad3 mediates ANG II-induced hypertensive kidney disease in mice. Am J Physiol Renal Physiol. 2012;302:F986-97 pubmed publisher
    ..Results from this study suggest that inhibition of Smad3 or overexpression of Smad7 may be a novel therapeutic strategy for hypertensive nephropathy. ..
  24. Park J, Chu J, Tsou A, Diop R, Tang Z, Wang A, et al. The effect of matrix stiffness on the differentiation of mesenchymal stem cells in response to TGF-?. Biomaterials. 2011;32:3921-30 pubmed publisher
    ..These results provide insights of how substrate stiffness differentially regulates stem cell differentiation, and have significant implications for the design of biomaterials with appropriate mechanical property for tissue regeneration. ..
  25. Xiao J, Meng X, Huang X, Chung A, Feng Y, Hui D, et al. miR-29 inhibits bleomycin-induced pulmonary fibrosis in mice. Mol Ther. 2012;20:1251-60 pubmed publisher
    ..In conclusion, miR-29 is negatively regulated by TGF-?/Smad3 and has a therapeutic potential for pulmonary fibrosis. SB-mediated miR-29 gene therapy is a non-invasive therapeutic strategy for lung disease associated with fibrosis. ..
  26. 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
  27. Solomon E, Li H, Duhachek Muggy S, Syta E, Zolkiewska A. The role of SnoN in transforming growth factor beta1-induced expression of metalloprotease-disintegrin ADAM12. J Biol Chem. 2010;285:21969-77 pubmed publisher
    ..Identification of SnoN as a repressor of the ADAM12 gene should contribute to advances in the studies on the role of ADAM12 in tumor progression and in the development of other pathologies. ..
  28. Liu N, Tolbert E, Ponnusamy M, Yan H, Zhuang S. Delayed administration of suramin attenuates the progression of renal fibrosis in obstructive nephropathy. J Pharmacol Exp Ther. 2011;338:758-66 pubmed publisher
  29. Cohen Solal K, Merrigan K, Chan J, Goydos J, Chen W, Foran D, et al. Constitutive Smad linker phosphorylation in melanoma: a mechanism of resistance to transforming growth factor-?-mediated growth inhibition. Pigment Cell Melanoma Res. 2011;24:512-24 pubmed publisher
    ..These results suggest that the linker phosphorylation of Smad3 contributes to the resistance of melanoma cells to TGF?-mediated growth inhibition. ..
  30. Xie W, Li Z, Miano J, Long X, Chen S. Smad3-mediated myocardin silencing: a novel mechanism governing the initiation of smooth muscle differentiation. J Biol Chem. 2011;286:15050-7 pubmed publisher
    ..Moreover, Smad3 inhibited Nkx2.5-activated Myocd promoter activity in a dose-dependent manner. Taken together, our results reveal a novel mechanism for Smad3-mediated inhibition of Myocd in the initiation phase of SMC differentiation. ..
  31. Huang X, Chung A, Yang F, Yue W, Deng C, Lau C, et al. Smad3 mediates cardiac inflammation and fibrosis in angiotensin II-induced hypertensive cardiac remodeling. Hypertension. 2010;55:1165-71 pubmed publisher
    ..In conclusion, Smad3 plays an essential role in hypertensive cardiac remodeling. Results from this study suggest that targeting Smad3 may be a novel therapeutic strategy for hypertensive cardiovascular disease. ..
  32. Shimizu C, Jain S, Hibberd M, Lin K, Molkara D, Frazer J, et al. Transforming growth factor-beta signaling pathway in patients with Kawasaki disease. Circ Cardiovasc Genet. 2011;4:16-25 pubmed publisher
    ..Analysis of transcript abundance and protein levels further support the importance of this pathway in KD pathogenesis. ..
  33. Brown S, Teo A, Pauklin S, Hannan N, Cho C, Lim B, et al. Activin/Nodal signaling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitors. Stem Cells. 2011;29:1176-85 pubmed publisher
  34. Michael D, Salter R, Ramji D. TGF-? inhibits the uptake of modified low density lipoprotein by human macrophages through a Smad-dependent pathway: a dominant role for Smad-2. Biochim Biophys Acta. 2012;1822:1608-16 pubmed publisher
  35. 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
    ..The authors provide further insight into the phenotype of AOS with SMAD3 mutations, and present recommendations for a clinical work-up. ..
  36. de Figueiredo Pontes L, Assis P, Santana Lemos B, Jacomo R, Lima A, Garcia A, et al. Halofuginone has anti-proliferative effects in acute promyelocytic leukemia by modulating the transforming growth factor beta signaling pathway. PLoS ONE. 2011;6:e26713 pubmed publisher
    ..Since loss of the TGF? response in leukemic cells may be an important second oncogenic hit, modulation of TGF? signaling may be of therapeutic interest. ..
  37. Royce S, Cheng V, Samuel C, Tang M. The regulation of fibrosis in airway remodeling in asthma. Mol Cell Endocrinol. 2012;351:167-75 pubmed publisher
  38. Estarás C, Akizu N, Garcia A, Beltran S, de la Cruz X, Martínez Balbás M. Genome-wide analysis reveals that Smad3 and JMJD3 HDM co-activate the neural developmental program. Development. 2012;139:2681-91 pubmed publisher
    ..Overall, these findings indicate that JMJD3 function is required for the TGF? developmental program to proceed. ..
  39. Pandit K, Corcoran D, Yousef H, Yarlagadda M, Tzouvelekis A, Gibson K, et al. Inhibition and role of let-7d in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2010;182:220-9 pubmed publisher
    ..Clinical trial registered with (NCT 00258544). ..
  40. Tapia Gonzalez S, Giraldez Perez R, Cuartero M, Casarejos M, Mena M, Wang X, et al. Dopamine and ?-synuclein dysfunction in Smad3 null mice. Mol Neurodegener. 2011;6:72 pubmed publisher
    ..These data underline a role for Smad3 in ?-synuclein and DA homeostasis, and suggest that modulatory molecules of this signalling pathway should be evaluated as possible neuroprotective agents. ..
  41. Lencioni K, Drivdahl R, Seamons A, Treuting P, Brabb T, Maggio Price L. Lack of effect of murine norovirus infection on a mouse model of bacteria-induced colon cancer. Comp Med. 2011;61:219-26 pubmed
    ..In addition, MNV infection alone did not result in IBD or colon cancer. Therefore MNV infection alone or in conjunction with Helicobacter does not alter the development or progression of IBD or colon cancer in Smad3(-/-) mice. ..
  42. Qin W, Chung A, Huang X, Meng X, Hui D, Yu C, et al. TGF-?/Smad3 signaling promotes renal fibrosis by inhibiting miR-29. J Am Soc Nephrol. 2011;22:1462-74 pubmed publisher
    ..In conclusion, miR-29 is a downstream inhibitor of TGF-?/Smad3-mediated fibrosis and may have therapeutic potential for diseases involving fibrosis. ..
  43. Webber J, Steadman R, Mason M, Tabi Z, Clayton A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 2010;70:9621-30 pubmed publisher
    ..This hitherto unknown trigger for instigating cellular differentiation in a distinctive manner has major implications for mechanisms underlying cancer-recruited stroma, fibrotic diseases, and wound-healing responses. ..
  44. Zhou B, Liu Y, Kahn M, Ann D, Han A, Wang H, et al. Interactions between ?-catenin and transforming growth factor-? signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem. 2012;287:7026-38 pubmed publisher
    ..These findings suggest a new therapeutic approach to pulmonary fibrosis by specifically uncoupling CBP/catenin-dependent signaling downstream of TGF-?. ..
  45. Liu N, Guo J, Pang M, Tolbert E, Ponnusamy M, Gong R, et al. Genetic or pharmacologic blockade of EGFR inhibits renal fibrosis. J Am Soc Nephrol. 2012;23:854-67 pubmed publisher
    ..Inhibition of EGFR may have therapeutic potential for fibrotic kidney disease...
  46. Takimoto T, Wakabayashi Y, Sekiya T, Inoue N, Morita R, Ichiyama K, et al. Smad2 and Smad3 are redundantly essential for the TGF-beta-mediated regulation of regulatory T plasticity and Th1 development. J Immunol. 2010;185:842-55 pubmed publisher
    ..However, TGF-beta-mediated induction of RORgamma t, a master regulator of Th17 cell, was independent of both Smad2 and Smad3, suggesting that TGF-beta regulates Th17 development through Smad2/3-dependent and -independent mechanisms. ..
  47. Tarasewicz E, Jeruss J. Phospho-specific Smad3 signaling: impact on breast oncogenesis. Cell Cycle. 2012;11:2443-51 pubmed publisher
    ..This review highlights recent advances revealing the critical role of phospho-specific Smad3 in malignancy and illustrates the potential prognostic and therapeutic impact of Smad3 phospho-isoforms in breast cancer. ..
  48. Tan C, Leuenberger N, Tan M, Yan Y, Chen Y, Kambadur R, et al. Smad3 deficiency in mice protects against insulin resistance and obesity induced by a high-fat diet. Diabetes. 2011;60:464-76 pubmed publisher
    ..Smad3 is a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes, suggesting that Smad3 may be a potential target for the treatment of obesity and its associated disorders. ..
  49. Lasfar A, Cohen Solal K. Resistance to transforming growth factor ?-mediated tumor suppression in melanoma: are multiple mechanisms in place?. Carcinogenesis. 2010;31:1710-7 pubmed publisher
    ..In addition, we propose additional models of resistance taking into consideration the information available on the dysregulation of fundamental cellular effectors and signaling pathways in melanoma. ..
  50. Li T, Gao L, Sheu T, Sampson E, Flick L, Konttinen Y, et al. Aberrant hypertrophy in Smad3-deficient murine chondrocytes is rescued by restoring transforming growth factor beta-activated kinase 1/activating transcription factor 2 signaling: a potential clinical implication for osteoarthritis. Arthritis Rheum. 2010;62:2359-69 pubmed publisher
    ..ATF-2 and p38 activation inhibit chondrocyte hypertrophy. Modulation of p38 isoform activity may provide a new therapeutic approach for OA. ..
  51. 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
    ..Thus, our data support a model in which Smurf2 negatively regulates TGF-β signalling by attenuating the activity of Smad3 rather than promoting its degradation. ..
  52. Hamby M, Hewett J, Hewett S. Smad3-dependent signaling underlies the TGF-?1-mediated enhancement in astrocytic iNOS expression. Glia. 2010;58:1282-91 pubmed publisher
    ..Overall, this data suggests that ALK5 signaling and Smad3 nuclear accumulation is required for optimal enhancement of LPS plus IFNgamma-induced NO production in astrocytes by TGF-beta1. ..