Genomes and Genes
Summary: An inhibitory Smad protein that negatively regulates the SIGNAL TRANSDUCTION PATHWAYS from BONE MORPHOGENETIC PROTEIN RECEPTORS. Smad6 inhibits PHOSPHORYLATION of SMAD2 PROTEIN and SMAD3 PROTEIN.
- Urano T, Shiraki M, Usui T, Sasaki N, Ouchi Y, Inoue S. Bone mass effects of a Smad6 gene polymorphism in Japanese postmenopausal women. J Bone Miner Metab. 2009;27:562-6 pubmed publisher..10 +/- 1.48; P = 0.0050). These findings suggest that the Smad6 gene is a candidate for the genetic determinants of BMD in postmenopausal women, and this SNP could be useful as a genetic marker for predicting the risk of osteoporosis. ..
- 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..Collectively, these findings reveal that Smad6 serves as a critical mediator of BMP signal via a functional interaction with Tbx6, thus regulating the activation of Tbx6 downstream genes during cell differentiation. ..
- Kleeff J, Maruyama H, Friess H, Buchler M, Falb D, Korc M. Smad6 suppresses TGF-beta-induced growth inhibition in COLO-357 pancreatic cancer cells and is overexpressed in pancreatic cancer. Biochem Biophys Res Commun. 1999;255:268-73 pubmed..Thus, enhanced expression of the TGF-beta signaling inhibitor Smad6 in pancreatic cancer may present a novel mechanism of TGF-beta resistance, which might have the potential to enhance the transformed phenotype of human cancer cells. ..
- Zuzarte Luis V, Montero J, Rodriguez Leon J, Merino R, Rodriguez Rey J, Hurle J. A new role for BMP5 during limb development acting through the synergic activation of Smad and MAPK pathways. Dev Biol. 2004;272:39-52 pubmed..Together, our results suggest that Smad and MAPK pathways act synergistically in the BMP pathway controlling limb development. ..
- 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..Mating Smad6 and Smurf1 transgenic mice produced double-transgenic pups with more delayed endochondral ossification than Smad6 transgenic mice. These results provided evidence that Smurf1 supports Smad6 function in vivo. ..
- Afrakhte M, Moren A, Jossan S, Itoh S, Sampath K, Westermark B, et al. Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members. Biochem Biophys Res Commun. 1998;249:505-11 pubmed..Thus, expression of inhibitory Smads is induced by multiple stimuli, including the various TGF-beta family members, whose action they antagonize. ..
- Huang H, Ma C, Yang M, Tang C, Wang H. Adrenomedullin impairs the profibrotic effects of transforming growth factor-beta1 through recruiting Smad6 protein in human renal tubular cells. Cell Physiol Biochem. 2005;15:117-24 pubmed..exerted no effect on TGF-beta1-induced Smad2 phosphorylation, but prevented the suppression of the inhibitory Smad6 protein by TGF-beta1 and restored Smad2-Samd6 complex formation...
- Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, et al. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem. 2001;276:12477-80 pubmed..These results thus reveal a novel function of Smad7, i.e. induction of degradation of TbetaR-I through recruitment of an E3 ligase to the receptor. ..
- Yin J, Lu K, Lin J, Wu L, Hildebrandt M, Chang D, et al. Genetic variants in TGF-Î² pathway are associated with ovarian cancer risk. PLoS ONE. 2011;6:e25559 pubmed publisher..Our findings suggest that genetic variants in the TGF-Î² signaling pathway are associated with ovarian cancer risk and may facilitate the identification of high-risk subgroups in the general population. ..
- Fujii M, Takeda K, Imamura T, Aoki H, Sampath T, Enomoto S, et al. Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation. Mol Biol Cell. 1999;10:3801-13 pubmed..Osteoblast differentiation induced by BMPs is thus mediated mainly via the Smad-signaling pathway, whereas chondrogenic differentiation may be transmitted by Smad-dependent and independent pathways. ..
- Jeon H, Dracheva T, Yang S, Meerzaman D, Fukuoka J, Shakoori A, et al. SMAD6 contributes to patient survival in non-small cell lung cancer and its knockdown reestablishes TGF-beta homeostasis in lung cancer cells. Cancer Res. 2008;68:9686-92 pubmed publisher..These results jointly suggest that SMAD6 plays a critical role in supporting lung cancer cell growth and survival. Targeted inactivation of SMAD6 may provide a novel therapeutic strategy for lung cancers expressing this gene. ..
- 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)...
- Nakayama T, Gardner H, Berg L, Christian J. Smad6 functions as an intracellular antagonist of some TGF-beta family members during Xenopus embryogenesis. Genes Cells. 1998;3:387-94 pubmed..We also find that Smad6 protein accumulates at the membrane in some cells but is partially or completely restricted to nuclei of most ..
- Nishihara A, Fujii M, Sampath T, Miyazono K, Reddi A. Bone morphogenetic protein signaling in articular chondrocyte differentiation. Biochem Biophys Res Commun. 2003;301:617-22 pubmed..These results together strongly suggest that induction of chondrocyte differentiation by BMP-7 is regulated by Smad pathways. ..
- Wang D, Kanuma T, Mizumuma H, Ibuki Y, Takenoshita S. Mutation analysis of the Smad6 and Smad7 gene in human ovarian cancers. Int J Oncol. 2000;17:1087-91 pubmed..Because these polymorphisms were not accompanied by amino acid substitution, the present results show that the mutations in the Smad6 and Smad7 genes are unlikely to be involved in human ovarian cancers. ..
- Osawa H, Nakajima M, Kato H, Fukuchi M, Kuwano H. Prognostic value of the expression of Smad6 and Smad7, as inhibitory Smads of the TGF-beta superfamily, in esophageal squamous cell carcinoma. Anticancer Res. 2004;24:3703-9 pubmed..0078 and p = 0.0207, respectively). Smad6 and Smad7 expression affects the progression of early lesions of esophageal SCC and indicates a poor prognosis. ..
- Bai S, Shi X, Yang X, Cao X. Smad6 as a transcriptional corepressor. J Biol Chem. 2000;275:8267-70 pubmed..These data indicate that Smad6 interacts with Hox transcription factors as part of the negative feedback circuit in the BMP signaling pathway. ..
- Hata A, Lagna G, Massague J, Hemmati Brivanlou A. Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev. 1998;12:186-97 pubmed..Smad6 specifically competes with Smad4 for binding to receptor-activated Smad1, yielding an apparently inactive Smad1-Smad6 complex. Therefore, Smad6 selectively antagonizes BMP-activated Smad1 by acting as a Smad4 decoy. ..
- Wang Q, Wei X, Zhu T, Zhang M, Shen R, Xing L, et al. Bone morphogenetic protein 2 activates Smad6 gene transcription through bone-specific transcription factor Runx2. J Biol Chem. 2007;282:10742-8 pubmed..Treatment with BMP-2 and transfection of Smad1 abolished Smurf1 binding to the OSE2 site. These results show that Smad1 binding excludes Smurf1 interaction with the OSE2 site and promotes Smad6 gene transcription. ..
- Kato S, Ueda S, Tamaki K, Fujii M, Miyazono K, ten Dijke P, et al. Ectopic expression of Smad7 inhibits transforming growth factor-beta responses in vascular smooth muscle cells. Life Sci. 2001;69:2641-52 pubmed..Our data indicate that Smads mediate TGF-beta responses on SMC phenotypes. Smad7, but not Smad6, may specifically act as an inhibitor of TGF-beta responses. ..
- Nakao A, Fujii M, Matsumura R, Kumano K, Saito Y, Miyazono K, et al. Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. J Clin Invest. 1999;104:5-11 pubmed..These data indicated that gene transfer of Smad7 (but not Smad6) prevented bleomycin-induced lung fibrosis, suggesting that Smad7 may have applicability in the treatment of pulmonary fibrosis. ..
- Otani H, Otsuka F, Inagaki K, Takeda M, Miyoshi T, Suzuki J, et al. Antagonistic effects of bone morphogenetic protein-4 and -7 on renal mesangial cell proliferation induced by aldosterone through MAPK activation. Am J Physiol Renal Physiol. 2007;292:F1513-25 pubmed
- de Almeida I, Rolo A, Batut J, Hill C, Stern C, Linker C. Unexpected activities of Smad7 in Xenopus mesodermal and neural induction. Mech Dev. 2008;125:421-31 pubmed publisher..We suggest that experiments relying on Smad7 as an inhibitor of TGFbeta-pathways should be interpreted with considerable caution. ..
- Ogawa K, Saito A, Matsui H, Suzuki H, Ohtsuka S, Shimosato D, et al. Activin-Nodal signaling is involved in propagation of mouse embryonic stem cells. J Cell Sci. 2007;120:55-65 pubmed..These findings suggest that endogenously activated autocrine loops of activin-Nodal signaling promote ES cell self-renewal. ..
- Glesne D, Huberman E. Smad6 is a protein kinase X phosphorylation substrate and is required for HL-60 cell differentiation. Oncogene. 2006;25:4086-98 pubmed..nuclear compartment of HL-60 cells during their macrophage differentiation where PrKX levels are induced and Smad6 protein levels remain relatively constant while levels of serine phosphorylation of Smad6 increase...
- Azuma H, Ehata S, Miyazaki H, Watabe T, Maruyama O, Imamura T, et al. Effect of Smad7 expression on metastasis of mouse mammary carcinoma JygMC(A) cells. J Natl Cancer Inst. 2005;97:1734-46 pubmed..Smad7 inhibits metastasis, possibly by regulating cell-cell adhesion. Systemic expression of Smad7 may be a novel strategy for the prevention of metastasis of advanced cancers. ..
- 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..Therefore, our findings provide insight into the molecular mechanisms underlying negative regulation of noncanonical TGF-? pathways. ..
- Sato M, Kawai Kowase K, Sato H, Oyama Y, Kanai H, Ohyama Y, et al. c-Src and hydrogen peroxide mediate transforming growth factor-beta1-induced smooth muscle cell-gene expression in 10T1/2 cells. Arterioscler Thromb Vasc Biol. 2005;25:341-7 pubmed..These results indicate that c-Src and hydrogen peroxide are required for TGF-beta1 signaling. ..
- 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..These data indicate an important role for Smad6 and Smad7 in glomerular cells in vivo that could be important for the cell homeostasis in physiologic and pathologic conditions. ..
- Yano M, Inoue Y, Tobimatsu T, Hendy G, Canaff L, Sugimoto T, et al. Smad7 inhibits differentiation and mineralization of mouse osteoblastic cells. Endocr J. 2012;59:653-62 pubmed..Therefore, I-Smads are important molecular targets for the negative control of bone formation. ..
- Kloen P, Lauzier D, Hamdy R. Co-expression of BMPs and BMP-inhibitors in human fractures and non-unions. Bone. 2012;51:59-68 pubmed publisher..An imbalance between the local presence of BMP and BMP-inhibitors may switch the direction towards healing or non-healing of a fracture. ..
- Khan J, Mandal T, Das T, Singh Y, Pillai B, Maiti S. Magnetite (Fe3O4) nanocrystals affect the expression of genes involved in the TGF-beta signalling pathway. Mol Biosyst. 2011;7:1481-6 pubmed publisher..As TGF-beta signaling invokes different responses in undifferentiated cells and adult tissues in a cell-type specific manner, our findings have far reaching implications in cellular development, differentiation and cancer. ..
- Zhu H, Burgess A. Regulation of transforming growth factor-beta signaling. Mol Cell Biol Res Commun. 2001;4:321-30 pubmed..The combined effects of the positive and/or negative TGF-beta controlled gene expression together with the endogenous protein set of the target cell are responsible for the multiplicity of biological functions. ..
- Zhang J, Li R, He Q, Li W, Niu B, Cheng N, et al. All-trans-retinoic acid alters Smads expression in embryonic neural tissue of mice. J Appl Toxicol. 2009;29:364-6 pubmed publisher..Data suggest that disruption of Smad signaling may be involved in ATRA-induced neural tube defects. ..
- Attisano L, Silvestri C, Izzi L, Labbe E. The transcriptional role of Smads and FAST (FoxH1) in TGFbeta and activin signalling. Mol Cell Endocrinol. 2001;180:3-11 pubmed..Thus, it is the interaction of Smads with a wide range of specific transcriptional partners that is important for the generation of diverse biological responses to TGFbeta superfamily members. ..
- Itoh F, Asao H, Sugamura K, Heldin C, ten Dijke P, Itoh S. Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. EMBO J. 2001;20:4132-42 pubmed..The data strongly suggest that the molecular mechanism by which AMSH exerts its action is by inhibiting the binding of Smad6 to activated type I receptors or activated R-Smads. ..
- Brodin G, ten Dijke P, Funa K, Heldin C, Landstrom M. Increased smad expression and activation are associated with apoptosis in normal and malignant prostate after castration. Cancer Res. 1999;59:2731-8 pubmed..Our results suggest that the signal transduction pathway for TGF-beta, leading to apoptosis, is activated in the normal prostate after castration and in the tumor model after castration, without or with estrogen treatment. ..
- Wang S, Sun A, Li L, Zhao G, Jia J, Wang K, et al. Up-regulation of BMP-2 antagonizes TGF-?1/ROCK-enhanced cardiac fibrotic signalling through activation of Smurf1/Smad6 complex. J Cell Mol Med. 2012;16:2301-10 pubmed publisher..In conclusion, we propose that BMP-2, as a novel fibrosis antagonizing cytokine, may have potential beneficial effect in attenuating pressure overload-induced cardiac fibrosis. ..
- Miyazono K. TGF-beta signaling by Smad proteins. Cytokine Growth Factor Rev. 2000;11:15-22 pubmed..Through interaction with different transcription factors and transcriptional co-activators or co-repressors, Smads may exhibit specific effects in various cell types. ..
- Singh P, Wig J, Srinivasan R, Radotra B. A comprehensive examination of Smad4, Smad6 and Smad7 mRNA expression in pancreatic ductal adenocarcinoma. Indian J Cancer. 2011;48:170-4 pubmed publisher..The absence of concordance between SMAD4 gene status, mRNA expression and Smad4 protein expression suggests the presence of other regulatory mechanisms in Smad4 transcription and translation in PDAC. ..
- Hazen V, Phan K, Hudiburgh S, Butler S. Inhibitory Smads differentially regulate cell fate specification and axon dynamics in the dorsal spinal cord. Dev Biol. 2011;356:566-75 pubmed publisher..In contrast, Smad6 most potently functions to block dI1 axon outgrowth. Taken together, these experiments suggest that the I-Smads have distinct roles in spatially limiting the response of cells to BMP signaling. ..
- Yu H, Mrowietz U, Seifert O. Downregulation of SMAD2, 4 and 6 mRNA and TGFbeta receptor I mRNA in lesional and non-lesional psoriatic skin. Acta Derm Venereol. 2009;89:351-6 pubmed publisher..The results of this study suggest that the expression of TGFbeta isoforms, receptors and SMADs may be involved in the increased proliferation of keratinocytes in psoriatic skin. ..
- Sandusky G, Berg D, Richardson M, Myers L, Grinnell B. Modulation of thrombomodulin-dependent activation of human protein C through differential expression of endothelial Smads. J Biol Chem. 2002;277:49815-9 pubmed..In contrast, the opposite expression pattern was observed for Smad7. Overall, our results suggest that the relative balance of these intracellular Smads modulate the balance of endothelial function with regard to protein C activation. ..
- 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. ..
- Scharstuhl A, Diepens R, Lensen J, Vitters E, van Beuningen H, van der Kraan P, et al. Adenoviral overexpression of Smad-7 and Smad-6 differentially regulates TGF-beta-mediated chondrocyte proliferation and proteoglycan synthesis. Osteoarthritis Cartilage. 2003;11:773-82 pubmed..We conclude that in chondrocytes distinct TGF-beta activities are differentially regulated by Smad-6 and Smad-7. ..
- Kaiser M, Haag J, Soder S, Bau B, Aigner T. Bone morphogenetic protein and transforming growth factor beta inhibitory Smads 6 and 7 are expressed in human adult normal and osteoarthritic cartilage in vivo and are differentially regulated in vitro by interleukin-1beta. Arthritis Rheum. 2004;50:3535-40 pubmed..The regulation in chondrocytes of Smad6 and Smad7 expression by IL-1beta suggests a potentially important role of IL-1beta signaling in chondrocytes, via indirect influencing of the BMP/TGFbeta signaling cascade. ..
- Nakao Y, Koike T, Ohta Y, Manaka T, Imai Y, Takaoka K. Parathyroid hormone enhances bone morphogenetic protein activity by increasing intracellular 3', 5'-cyclic adenosine monophosphate accumulation in osteoblastic MC3T3-E1 cells. Bone. 2009;44:872-7 pubmed publisher..These results suggest that PTH enhances BMP signaling when PTH-induced intracellular cAMP level is maintained for a few hours, accelerating BMP actions to promote osteoblastic function and anabolic actions of new bone formation. ..
- Elshaier A, Hakimiyan A, Rappoport L, Rueger D, Chubinskaya S. Effect of interleukin-1beta on osteogenic protein 1-induced signaling in adult human articular chondrocytes. Arthritis Rheum. 2009;60:143-54 pubmed publisher..These findings describe new mechanisms of the crosstalk between OP-1 and IL-1beta in chondrocytes. The study also identifies potential targets for therapeutic interventions in the treatment of cartilage-degenerative processes. ..
- Amano K, Ichida F, Sugita A, Hata K, Wada M, Takigawa Y, et al. MSX2 stimulates chondrocyte maturation by controlling Ihh expression. J Biol Chem. 2008;283:29513-21 pubmed publisher..Collectively, our results indicated that Msx2 promotes the maturation of chondrocytes, at least in part, through up-regulating Ihh expression. ..
- 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
- 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..Both wild-type and Smad6R74A were equally efficient in blocking BMP-induced growth arrest upon their ectopic expression in HS-72 mouse B-cell hybridoma cells. ..
- Hirao M, Tamai N, Tsumaki N, Yoshikawa H, Myoui A. Oxygen tension regulates chondrocyte differentiation and function during endochondral ossification. J Biol Chem. 2006;281:31079-92 pubmed..These hypoxia-induced phenomena may act on chondrocytes to enhance and preserve their phenotype and function during chondrocyte differentiation and endochondral ossification. ..
- Olivey H, Mundell N, Austin A, Barnett J. Transforming growth factor-beta stimulates epithelial-mesenchymal transformation in the proepicardium. Dev Dyn. 2006;235:50-9 pubmed..These data demonstrate that TGFbeta stimulates transformation in the PE and suggest that ALK2 partially mediates this effect. ..