Gene Symbol: Smad6
Description: SMAD family member 6
Alias: Madh6, b2b390Clo, mothers against decapentaplegic homolog 6, MAD homolog 6, Smad 6, mad homolog 7, mothers against DPP homolog 6
Species: mouse
Products:     Smad6

Top Publications

  1. Flanders K, Kim E, Roberts A. Immunohistochemical expression of Smads 1-6 in the 15-day gestation mouse embryo: signaling by BMPs and TGF-betas. Dev Dyn. 2001;220:141-54 pubmed
    ..tissues express Smad 4 and at least one each of the BMP-specific and TGF-beta-specific Smads, while expression of Smad 6 is more restricted...
  2. Ma L, Lu M, Schwartz R, Martin J. Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development. 2005;132:5601-11 pubmed
    ..Our data indicate that Bmp2 has a crucial role in coordinating multiple aspects of AV canal morphogenesis. ..
  3. Galvin K, Donovan M, Lynch C, Meyer R, Paul R, Lorenz J, et al. A role for smad6 in development and homeostasis of the cardiovascular system. Nat Genet. 2000;24:171-4 pubmed
    ..Here we explore the role of an inhibitory Smad in vivo by targeted mutation of Madh6 (which encodes the Smad6 protein)...
  4. 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. ..
  5. Kim E, Kim B. Lipopolysaccharide inhibits transforming growth factor-beta1-stimulated Smad6 expression by inducing phosphorylation of the linker region of Smad3 through a TLR4-IRAK1-ERK1/2 pathway. FEBS Lett. 2011;585:779-85 pubmed publisher
    b>Smad6, one of the inhibitory Smads, plays an important role in transforming growth factor-beta1 (TGF-?1)-mediated negative regulation of pro-inflammatory signaling...
  6. Chen Y, Liu B, Zhou Z, Hu R, Fei C, Xie Z, et al. Smad6 inhibits the transcriptional activity of Tbx6 by mediating its degradation. J Biol Chem. 2009;284:23481-90 pubmed publisher
    ..Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal...
  7. Datta P, Chytil A, Gorska A, Moses H. Identification of STRAP, a novel WD domain protein in transforming growth factor-beta signaling. J Biol Chem. 1998;273:34671-4 pubmed
    ..It also shows synergistic inhibition of TGF-beta signaling in concert with Smad7, but not with Smad6, as measured by TGF-beta-dependent transcriptional reporters...
  8. Christian J, Nakayama T. Can't get no SMADisfaction: Smad proteins as positive and negative regulators of TGF-beta family signals. Bioessays. 1999;21:382-90 pubmed
    ..Negative feedback circuits such as these play important roles in fine-tuning the activity of multifunctional signaling molecules during embryonic patterning and in response to pathologic stimuli in adults. ..
  9. MacGrogan D, D Amato G, Travisano S, Martínez Poveda B, Luxan G, del Monte Nieto G, et al. Sequential Ligand-Dependent Notch Signaling Activation Regulates Valve Primordium Formation and Morphogenesis. Circ Res. 2016;118:1480-97 pubmed publisher
    ..Our studies identify a mechanism of signaling cross talk during valve morphogenesis involved in the origin of congenital heart defects associated with reduced NOTCH function. ..

More Information


  1. Wang J, Greene S, Bonilla Claudio M, Tao Y, Zhang J, Bai Y, et al. Bmp signaling regulates myocardial differentiation from cardiac progenitors through a MicroRNA-mediated mechanism. Dev Cell. 2010;19:903-12 pubmed publisher
    ..Our findings indicate that Bmp signaling directly regulates a miRNA-mediated effector mechanism that downregulates cardiac progenitor genes and enhances myocardial differentiation. ..
  2. Iwai T, Murai J, Yoshikawa H, Tsumaki N. Smad7 Inhibits chondrocyte differentiation at multiple steps during endochondral bone formation and down-regulates p38 MAPK pathways. J Biol Chem. 2008;283:27154-64 pubmed publisher
    ..showed that BMP-induced cartilaginous nodule formation was down-regulated by overexpression of Smad7, but not Smad6. Overexpression of Smad7, but not Smad6, down-regulated the phosphorylation of p38 MAPKs...
  3. Davis R, Harding M, Moayedi Y, Mardon G. Mouse Dach1 and Dach2 are redundantly required for Müllerian duct development. Genesis. 2008;46:205-13 pubmed publisher
    ..This vertebrate Dach1/2 function may have been conserved during arthropod evolution, as Drosophila dachshund mutants also exhibit an FRT phenotype. ..
  4. Liu H, Liu Y, Viggeswarapu M, Zheng Z, Titus L, Boden S. Activation of c-Jun NH(2)-terminal kinase 1 increases cellular responsiveness to BMP-2 and decreases binding of inhibitory Smad6 to the type 1 BMP receptor. J Bone Miner Res. 2011;26:1122-32 pubmed publisher
    ..for BMP-2-induced formation of mineralized nodules, and (3) JNK1 activation decreases binding of inhibitory Smad6 to the type I BMP receptor (BMPR-I) and reciprocally increases binding of Smad1, both observations that would ..
  5. Gaussin V, Van de Putte T, Mishina Y, Hanks M, Zwijsen A, Huylebroeck D, et al. Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3. Proc Natl Acad Sci U S A. 2002;99:2878-83 pubmed
    ..Hence, ALK3 is essential, beyond just the egg cylinder stage, for myocyte-dependent functions and signals in cardiac organogenesis. ..
  6. Sultana H, Neelakanta G, Foellmer H, Montgomery R, Anderson J, Koski R, et al. Semaphorin 7A contributes to West Nile virus pathogenesis through TGF-?1/Smad6 signaling. J Immunol. 2012;189:3150-8 pubmed publisher
    ..Furthermore, Sema7A positively regulates the production of TGF-?1 and Smad6 to facilitate WNV pathogenesis in mice...
  7. Yin Z, Haynie J, Yang X, Han B, Kiatchoosakun S, Restivo J, et al. The essential role of Cited2, a negative regulator for HIF-1alpha, in heart development and neurulation. Proc Natl Acad Sci U S A. 2002;99:10488-93 pubmed
    ..These findings demonstrate that Cited2 is an indispensable regulatory gene during prenatal development. ..
  8. Shen R, Chen M, Wang Y, Kaneki H, Xing L, O Keefe R, et al. Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation. J Biol Chem. 2006;281:3569-76 pubmed
    ..We performed immunoprecipitation assays and found that Smad6 but not Smad7 interacts with Runx2...
  9. Estrada K, Retting K, Chin A, Lyons K. Smad6 is essential to limit BMP signaling during cartilage development. J Bone Miner Res. 2011;26:2498-510 pubmed publisher
    ..In this study, we have determined the role of Smad6 in endochondral bone formation...
  10. Souilhol C, Gonneau C, Lendínez J, Batsivari A, Rybtsov S, Wilson H, et al. Inductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells. Nat Commun. 2016;7:10784 pubmed publisher
  11. Lin X, Liang Y, Sun B, Liang M, Shi Y, Brunicardi F, et al. Smad6 recruits transcription corepressor CtBP to repress bone morphogenetic protein-induced transcription. Mol Cell Biol. 2003;23:9081-93 pubmed
    b>Smad6 and Smad7 are inhibitory Smads induced by transforming growth factor beta-Smad signal transduction pathways in a negative-feedback mechanism...
  12. Kamiya Y, Miyazono K, Miyazawa K. Smad7 inhibits transforming growth factor-beta family type i receptors through two distinct modes of interaction. J Biol Chem. 2010;285:30804-13 pubmed publisher
    The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-? (TGF-?) family signaling...
  13. Liu W, Rui H, Wang J, Lin S, He Y, Chen M, et al. Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia. EMBO J. 2006;25:1646-58 pubmed
    ..However, coexpression of Wnt-1 reduced Smad7 ubiquitination by downregulating Axin levels, underscoring the importance of Axin as an intrinsic regulator in TGF-beta signaling. ..
  14. Lopez Escobar B, De Felipe B, Sánchez Alcázar J, Sasaki T, Copp A, Ybot Gonzalez P. Laminin and integrin expression in the ventral ectodermal ridge of the mouse embryo: implications for regulation of BMP signalling. Dev Dyn. 2012;241:1808-15 pubmed publisher
    ..Laminin532 could interact with α6-containing integrin to direct differentiation of the specialised VER cells from surface ectoderm. ..
  15. Moroishi T, Nishiyama M, Takeda Y, Iwai K, Nakayama K. The FBXL5-IRP2 axis is integral to control of iron metabolism in vivo. Cell Metab. 2011;14:339-51 pubmed publisher
    ..The liver-specific mutant mice died with acute liver failure when fed a high-iron diet. Thus, our results uncover a major role for FBXL5 in ensuring an appropriate supply of iron to cells. ..
  16. Schiffer M, Schiffer L, Gupta A, Shaw A, Roberts I, Mundel P, et al. Inhibitory smads and tgf-Beta signaling in glomerular cells. J Am Soc Nephrol. 2002;13:2657-66 pubmed
    b>Smad6 and Smad7 are inhibitory SMADs with putative functional roles at the intersection of major intracellular signaling networks, including TGF-beta, receptor tyrosine kinase (RTK), JAK/STAT, and NF-kappaB pathways...
  17. Flagg A, Earley J, Svensson E. FOG-2 attenuates endothelial-to-mesenchymal transformation in the endocardial cushions of the developing heart. Dev Biol. 2007;304:308-16 pubmed
    ..Taken together with GATA4's known role in promoting EMT, these results suggest that FOG-2 functions in cardiac valve formation as an attenuator of EMT by repressing GATA4 activity within the developing endocardial cushions. ..
  18. Morty R, Nejman B, Kwapiszewska G, Hecker M, Zakrzewicz A, Kouri F, et al. Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol. 2007;27:1072-8 pubmed
    ..BMP signaling and BMP-regulated physiological phenomena are perturbed in MCT-treated rats, lending solid support to the proposed roles for BMP signaling in the pathogenesis of human PAH. ..
  19. Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M, et al. Smad6 inhibits signalling by the TGF-beta superfamily. Nature. 1997;389:622-6 pubmed
    ..Here we report the isolation of Smad6 in the mouse...
  20. Horiki M, Imamura T, Okamoto M, Hayashi M, Murai J, Myoui A, et al. Smad6/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism with osteopenia. J Cell Biol. 2004;165:433-45 pubmed
    Biochemical experiments have shown that Smad6 and Smad ubiquitin regulatory factor 1 (Smurf1) block the signal transduction of bone morphogenetic proteins (BMPs). However, their in vivo functions are largely unknown...
  21. De Rosa L, Antonini D, Ferone G, Russo M, Yu P, Han R, et al. p63 Suppresses non-epidermal lineage markers in a bone morphogenetic protein-dependent manner via repression of Smad7. J Biol Chem. 2009;284:30574-82 pubmed publisher
    ..Our data indicate that p63 prevents ectopic expression of non-epidermal genes by a mechanism involving Smad7 repression and, to a lesser extent, Bmp7 induction, with consequent enhancement of BMP/Smad signaling. ..
  22. Inamitsu M, Itoh S, Hellman U, Ten Dijke P, Kato M. Methylation of Smad6 by protein arginine N-methyltransferase 1. FEBS Lett. 2006;580:6603-11 pubmed
    ..Here we demonstrate that inhibitory-Smads (Smad6 and Smad7), but not receptor-regulated- (R-)Smads and the common-partner Smad4, can be methylated by protein ..
  23. Jung S, Lee J, Park J, Oh Y, Lee S, Park J, et al. Smad6 inhibits non-canonical TGF-?1 signalling by recruiting the deubiquitinase A20 to TRAF6. Nat Commun. 2013;4:2562 pubmed publisher
    ..Here we demonstrate that the inhibitory Smad Smad6, but not Smad7, negatively regulates TGF-?1-induced activation of the TRAF6-TAK1-p38 MAPK/JNK pathway, a ..
  24. Heisig J, Weber D, Englberger E, Winkler A, Kneitz S, Sung W, et al. Target gene analysis by microarrays and chromatin immunoprecipitation identifies HEY proteins as highly redundant bHLH repressors. PLoS Genet. 2012;8:e1002728 pubmed publisher
    ..These data clearly establish the three HEY bHLH factors as highly redundant transcriptional repressors in vitro and in vivo, which explains the combinatorial action observed in different tissues with overlapping expression. ..
  25. Tsubakihara Y, Hikita A, Yamamoto S, Matsushita S, Matsushita N, Oshima Y, et al. Arkadia enhances BMP signalling through ubiquitylation and degradation of Smad6. J Biochem. 2015;158:61-71 pubmed publisher
    ..Furthermore, we showed that Smad6, a BMP-specific inhibitory Smad, is a target of Arkadia: wild-type (WT) Arkadia, but not the C937A (CA) mutant ..
  26. Lu X, Yao X, Yan C, Wan Q, Li Y. Functional role of NKX2-5 and Smad6 expression in developing rheumatic heart disease. Eur Rev Med Pharmacol Sci. 2016;20:715-20 pubmed
    ..The present investigation of NKX2-5 and Smad-6 in RHD provides a new insight of data that helps to understand the disease pathogenesis. ..
  27. Kang M, Bok J, Deocaris C, Park H, Kim M. Hoxc8 represses BMP-induced expression of Smad6. Mol Cells. 2010;29:29-33 pubmed publisher
    ..A well known feedback mechanism is a BMP-mediated induction of Smad6, an inhibitor of BMP signaling...
  28. Gitler A, Lu M, Jiang Y, Epstein J, Gruber P. Molecular markers of cardiac endocardial cushion development. Dev Dyn. 2003;228:643-50 pubmed
  29. Miyamoto T, Nakamura H, Nagashio Y, Asaumi H, Harada M, Otsuki M. Overexpression of Smad6 exacerbates pancreatic fibrosis in murine caerulein-induced chronic pancreatic injuries. Pancreas. 2010;39:385-91 pubmed publisher
    We examined the effect of the overexpression of Smad6 on pancreatic fibrosis after chronic pancreatic injury...
  30. Alejandre Alcazar M, Michiels Corsten M, Vicencio A, Reiss I, Ryu J, de Krijger R, et al. TGF-beta signaling is dynamically regulated during the alveolarization of rodent and human lungs. Dev Dyn. 2008;237:259-69 pubmed
    ..receptors Acvrl1, Tgfbr1, Tgfbr2, Tgfbr3, and endoglin, and the intracellular messengers Smad2, Smad3, Smad4, Smad6, and Smad7 were noted as mouse and human lungs progressed through the canalicular, saccular, and alveolar stages ..
  31. Li Q. Inhibitory SMADs: potential regulators of ovarian function. Biol Reprod. 2015;92:50 pubmed publisher
    ..components consisting of receptor-regulated SMADs (SMAD1/2/3/5/9), a common SMAD (SMAD4), and inhibitory SMADs (SMAD6/7)...
  32. Nishimura Y, Kurisaki A, Nakanishi M, Ohnuma K, Ninomiya N, Komazaki S, et al. Inhibitory Smad proteins promote the differentiation of mouse embryonic stem cells into ependymal-like ciliated cells. Biochem Biophys Res Commun. 2010;401:1-6 pubmed publisher
    ..In this study, we found that inhibitory Smad proteins, Smad7 and Smad6, significantly promoted the differentiation of mouse embryonic stem (ES) cells into ciliated cells...
  33. Vrljicak P, Myburgh D, Ryan A, Van Rooijen M, Mummery C, Gupta I. Smad expression during kidney development. Am J Physiol Renal Physiol. 2004;286:F625-33 pubmed
    ..R) Smads (Smad1, -2, -3, -5, and -8), the common partner Smad (Smad4), and the inhibitory (I) Smads (Smad6 and -7) were all expressed during mouse kidney development from embryonic day 12 until the end of nephrogenesis at ..
  34. Li X, Lim J, Lu J, Pedego T, Demer L, Tintut Y. Protective Role of Smad6 in Inflammation-Induced Valvular Cell Calcification. J Cell Biochem. 2015;116:2354-64 pubmed publisher
    ..Evidence suggests that inhibitory small mothers against decapentaplegic (I-Smads; Smad6 and 7) regulate valve embryogenesis and may serve as a mitigating factor in CAVD...
  35. Sugama R, Koike T, Imai Y, Nomura Furuwatari C, Takaoka K. Bone morphogenetic protein activities are enhanced by 3',5'-cyclic adenosine monophosphate through suppression of Smad6 expression in osteoprogenitor cells. Bone. 2006;38:206-14 pubmed
    ..a specific intracellular signaling cascade to target genes via R-Smads (Smad1,5,8), Co-Smad (Smad4) and I-Smads (Smad6,7)...
  36. Frieden L, Townsend T, Vaught D, Delaughter D, Hwang Y, Barnett J, et al. Regulation of heart valve morphogenesis by Eph receptor ligand, ephrin-A1. Dev Dyn. 2010;239:3226-34 pubmed publisher
    ..Taken together, these data indicate that ephrin-A1 regulates cardiac valve development, making ephrin-A1-deficient mice a novel model for congenital heart defects. ..
  37. Cho A, Tang Y, Davila J, Deng S, Chen L, Miller E, et al. Calcineurin signaling regulates neural induction through antagonizing the BMP pathway. Neuron. 2014;82:109-124 pubmed publisher
    ..As a result, FGF-activated CaN signaling opposes BMP signaling during gastrulation, thereby promoting neural induction and the development of anterior structures. ..
  38. Vujic Spasic M, Sparla R, Mleczko Sanecka K, Migas M, Breitkopf Heinlein K, Dooley S, et al. Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload. Biochim Biophys Acta. 2013;1832:76-84 pubmed publisher
    ..In this study we define the mRNA expression of the two functionally related Smad proteins, Smad6 and Smad7, within pathways known to regulate hepcidin levels...
  39. Greene R, Nugent P, Mukhopadhyay P, Warner D, Pisano M. Intracellular dynamics of Smad-mediated TGFbeta signaling. J Cell Physiol. 2003;197:261-71 pubmed
    ..Collectively, these data point to the presence of a functional Smad-mediated TGFbeta signaling system in cells of the developing murine palate. ..
  40. Simirskii V, Wang Y, Duncan M. Conditional deletion of beta1-integrin from the developing lens leads to loss of the lens epithelial phenotype. Dev Biol. 2007;306:658-68 pubmed
    ..lens epithelial cells upregulate the expression of alpha-smooth muscle actin and nuclear Smad4 and downregulate Smad6 suggesting that beta1-integrin may brake TGFbeta family signaling leading to epithelial-mesenchymal transitions in ..
  41. Bonilla Claudio M, Wang J, Bai Y, Klysik E, Selever J, Martin J. Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development. Development. 2012;139:709-19 pubmed publisher
    ..Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG signature, including Satb2, Smad6, Hand1, Gadd45? and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated ..
  42. Yang Y, Klingensmith J. Roles of organizer factors and BMP antagonism in mammalian forebrain establishment. Dev Biol. 2006;296:458-75 pubmed
    ..These results lead to a model in which BMP antagonism supplied by exogenous tissues promotes forebrain establishment and maintenance in the murine ectoderm. ..
  43. Shen Z, Braun R, Hu J, Xie Q, Chu H, Love R, et al. Pin1 protein regulates Smad protein signaling and pulmonary fibrosis. J Biol Chem. 2012;287:23294-305 pubmed publisher
    ..In Pin1(-/-) cells, inhibitory Smad6 was found in the cytoplasm rather than nucleus...
  44. Itman C, Loveland K. SMAD expression in the testis: an insight into BMP regulation of spermatogenesis. Dev Dyn. 2008;237:97-111 pubmed
    ..Smad1, Smad5, Smad8, Smad4, Smad6, and Smad7 expression is ubiquitous during testis development but becomes cell-specific in the adult...
  45. Gao Z, Kim G, MacKinnon A, Flagg A, Bassett B, Earley J, et al. Ets1 is required for proper migration and differentiation of the cardiac neural crest. Development. 2010;137:1543-51 pubmed publisher
  46. Snider P, Hinton R, Moreno Rodriguez R, Wang J, Rogers R, Lindsley A, et al. Periostin is required for maturation and extracellular matrix stabilization of noncardiomyocyte lineages of the heart. Circ Res. 2008;102:752-60 pubmed publisher
    ..Thus, peri(lacZ) knockouts provide a new model of viable latent valve disease. ..
  47. Ku M, Howard S, Ni W, Lagna G, Hata A. OAZ regulates bone morphogenetic protein signaling through Smad6 activation. J Biol Chem. 2006;281:5277-87 pubmed
    ..We demonstrate that upon BMP4 stimulation, an OAZ-Smad1/4 complex binds to and activates the gene encoding Smad6, a specific inhibitor of the BMP pathway...
  48. Islam S, Mokhtari R, Kumar S, Maalouf J, Arab S, Yeger H, et al. Spatio-temporal distribution of Smads and role of Smads/TGF-?/BMP-4 in the regulation of mouse bladder organogenesis. PLoS ONE. 2013;8:e61340 pubmed publisher
    ..b>Smad6 and Smad7 showed overlapping expression with R-Smads, which are critical for bladder development...
  49. Kelly C, Thymiakou E, Dixon J, Tanaka S, Godwin J, Episkopou V. Rnf165/Ark2C enhances BMP-Smad signaling to mediate motor axon extension. PLoS Biol. 2013;11:e1001538 pubmed publisher
    ..Together the above data reveal an involvement of BMP-Smad signaling in motor axon advancement. ..
  50. Kuratomi G, Komuro A, Goto K, Shinozaki M, Miyazawa K, Miyazono K, et al. NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor. Biochem J. 2005;386:461-70 pubmed
  51. Vincentz J, Firulli B, Lin A, Spicer D, Howard M, Firulli A. Twist1 controls a cell-specification switch governing cell fate decisions within the cardiac neural crest. PLoS Genet. 2013;9:e1003405 pubmed publisher
    ..These data demonstrate that Twist1 functions in post-migratory neural crest cells to repress pro-neural factors and thereby regulate cell fate determination between ectodermal and mesodermal lineages. ..
  52. Knezevic K, Bee T, Wilson N, Janes M, Kinston S, Polderdijk S, et al. A Runx1-Smad6 rheostat controls Runx1 activity during embryonic hematopoiesis. Mol Cell Biol. 2011;31:2817-26 pubmed publisher
    ..The transcription factors that upregulate the expression of Runx1 also upregulate the expression of Smad6, the inhibitory Smad, which controls Runx1 activity by targeting it to the proteasome...
  53. Goto K, Kamiya Y, Imamura T, Miyazono K, Miyazawa K. Selective inhibitory effects of Smad6 on bone morphogenetic protein type I receptors. J Biol Chem. 2007;282:20603-11 pubmed
    The inhibitory Smads, Smad6 and Smad7, play pivotal roles in negative regulation of transforming growth factor-beta (TGF-beta) family signaling as feedback molecules as well as mediators of cross-talk with other signaling pathways...