Skip to main content
SpringerLink
Log in

Inhibitory Smads: Mechanisms of Action and Roles in Human Diseases

  • Chapter
Smad Signal Transduction

Part of the book series: Proteins and Cell Regulation ((PROR,volume 5))

Abstract

Inhibitory Smads are one of the major inhibitory regulators of intracellular signaling mediated by TGF-β superfamily proteins. Inhibitory Smads repress TGF-β superfamily signaling by several different mechanisms at the levels of cellular membrane, cytoplasm, and nucleus. Importantly, expression of I-Smads is induced by TGF-β superfamily proteins themselves and other signaling pathways, indicating a key role for I-Smads in negative feedback or cross-talk control of TGF-β superfamily signaling. Probably, I-Smads tightly control intensity and duration of TGF-β superfamily signaling and maintain homeostasis. Indeed, there is accumulating evidence that aberrant I-Smads expression and activity contributes to human diseases induced by TGF-β superfamily proteins. Better understanding of the mechanisms underlying I-Smads regulation may thus provide novel therapeutic targets for diseases associated with TGF-β superfamily proteins

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Afrakhte, M., Morén, A., Jossan, S., Itoh, S., Sampath, K., Westermark, B., Heldin, C.-H., Heldin, N.-E., and ten Dijke, P., 1998, Induction of inhibitory Smad6 and Smad7 mRNA by TGF-β family members. Biochem Biophys Res Commun 249: 505-511.

    Article  PubMed  CAS  Google Scholar 

  • Asano, Y., Ihn, H., Yamane, K., Kubo, M., and Tamaki, K., 2004, Impaired Smad7-Smurf-mediated negative regulation of TGF-β signaling in scleroderma fibroblasts. J Clin Invest 113: 253-264.

    Article  PubMed  CAS  Google Scholar 

  • Bai, S., and Cao, X., 2002, A nuclear antagonistic mechanism of inhibitory Smads in transforming growth factor-β signaling. J Biol Chem 277: 4176-4182.

    Article  PubMed  CAS  Google Scholar 

  • Bai, S., Shi, X., Yang, X., and Cao, X., 2000, Smad6 as a transcriptional corepressor. J Biol Chem 275: 8267-8270.

    Article  PubMed  CAS  Google Scholar 

  • Benchabane H, Wrana JL. 2003, GATA- and Smad1-dependent enhancers in the Smad7 gene differentially interpret bone morphogenetic protein concentrations. Mol Cell Biol 23: 664661.

    Article  CAS  Google Scholar 

  • Bitzer, M., von Gersdorff, G., Liang, D., Dominguez-Rosales, A., Beg, A.A., Rojkind, M., and Böttinger, E.P., 2000, A mechanism of suppression of TGF-β/SMAD signaling by NF-κ B/RelA. Genes Dev 14: 187-197.

    PubMed  CAS  Google Scholar 

  • Boulay, J.L., Mild, G., Reuter, J., Lagrange, M., Terracciano, L., Lowy, A., Laffer, U., Orth, B., Metzger, U., Stamm, B., Martinoli, S., Herrmann, R., and Rochlitz, C., 2001, Combined copy status of 18q21 genes in colorectal cancer shows frequent retention of SMAD7. Genes Chromosomes Cancer 31: 240-247.

    Article  PubMed  CAS  Google Scholar 

  • Brodin, G., Åhgren, A., ten Dijke, P., Heldin, C.-H., and Heuchel, R., 2000, Efficient TGF-β induction of the Smad7 gene requires cooperation between AP-1, Sp1, and Smad proteins on the mouse Smad7 promoter. J Biol Chem 275: 29023-29030.

    Article  PubMed  CAS  Google Scholar 

  • Datta, P.K., and Moses, H.L., 2000, STRAP and Smad7 synergize in the inhibition of transforming growth factor β signaling. Mol Cell Biol 20: 3157-3167.

    Article  PubMed  CAS  Google Scholar 

  • Denissova, N.G., and Liu, F., 2004, Repression of endogenous Smad7 by Ski. J Biol Chem 279: 28143-28148.

    Article  PubMed  CAS  Google Scholar 

  • Denissova, N.G., Pouponnot, C., Long, J., He, D., and Liu, F., 2000, Transforming growth factor β-inducible independent binding of SMAD to the Smad7 promoter. Proc Natl Acad Sci U S A 97: 6397-6402.

    Article  PubMed  CAS  Google Scholar 

  • Dong, C., Zhu, S., Wang, T., Yoon, W., Li, Z., Alvarez, R.J., ten Dijke, P., White, B., Wigley, F.M., and Goldschmidt-Clermont, P.J., 2002, Deficient Smad7 expression: a putative molecular defect in scleroderma. Proc Natl Acad Sci U S A 99: 3908-3913.

    Article  PubMed  CAS  Google Scholar 

  • Dooley, S., Hamzavi, J., Breitkopf, K., Wiercinska, E., Said, H.M., Lorenzen, J., ten Dijke, P., and Gressner, A.M., 2003, Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats. Gastroenterology 125: 178-191.

    Article  PubMed  CAS  Google Scholar 

  • Ebisawa, T., Fukuchi, M., Murakami, G., Chiba, T., Tanaka, K., Imamura, T., and Miyazono, K., 2001, Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation. J Biol Chem 276: 12477-12480.

    Article  PubMed  CAS  Google Scholar 

  • Edlund, S., Bu, S., Schuster, N., Aspenström, P., Heuchel, R., Heldin, N.-E., ten Dijke, P., Heldin, C.-H., and Landström, M., 2003, Transforming growth factor-β1 (TGF-β)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-β-activated kinase 1 and mitogen-activated protein kinase kinase 3. Mol Biol Cell 14: 529-544.

    Article  PubMed  CAS  Google Scholar 

  • Edlund, S., Landström, M., Heldin, C.-H., and Aspenström, P., 2004, Smad7 is required for TGF-β-induced activation of the small GTPase Cdc42. J Cell Sci 117: 1835-1847.

    Article  PubMed  CAS  Google Scholar 

  • Ferrigno, O., Lallemand, F., Verrecchia, F., L’Hoste, S., Camonis, J., Atfi, A., Mauviel, A., 2002, Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-β/Smad signaling. Oncogene 21: 4879-4884.

    Article  PubMed  CAS  Google Scholar 

  • Fukasawa, H., Yamamoto, T., Togawa, A., Ohashi, N., Fujigaki, Y., Oda, T., Uchida, C., Kitagawa, K., Hattori, T., Suzuki, S., Kitagawa, M., and Hishida, A., 2004, Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice. Proc Natl Acad Sci U S A 101: 8687-8692.

    Article  PubMed  CAS  Google Scholar 

  • Galvin, K.M., Donovan, M.J., Lynch, C.A., Meyer, R.I., Paul, R.J., Lorenz, J.N., Fairchild-Huntress, V., Dixon, K.L., Dunmore, J.H., Gimbrone, M.A., Jr., Falb, D., and Huszar, D., 2000, A role for smad6 in development and homeostasis of the cardiovascular system. Nat Genet 24: 171-174.

    Article  PubMed  CAS  Google Scholar 

  • Grönroos, E., Hellman, U., Heldin, C.-H., and Ericsson, J., 2002, Control of Smad7 stability by competition between acetylation and ubiquitination. Mol Cell 10: 483-493.

    Article  PubMed  Google Scholar 

  • Halder SK, Beauchamp RD, Datta PK. 2005, Smad7 induces tumorigenicity by blocking TGF-β-induced growth inhibition and apoptosis. Exp Cell Res 307: 231-246.

    Article  PubMed  CAS  Google Scholar 

  • Hanyu, A., Ishidou, Y., Ebisawa, T., Shimanuki, T., Imamura, T., and Miyazono, K., 2001, The N domain of Smad7 is essential for specific inhibition of transforming growth factor-β signaling. J Cell Biol 155: 1017-1027.

    Article  PubMed  CAS  Google Scholar 

  • Hata, A., Lagna, G., Massagué, J., and Hemmati-Brivanlou, A., 1998, Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 12: 186-197.

    PubMed  CAS  Google Scholar 

  • Hayashi, H., Abdollah, S., Qiu, Y., Cai, J., Xu, Y.Y., Grinnell, B.W., Richardson, M.A., Topper, J.N., Gimbrone, M.A.J., Wrana, J.L., and Falb, D., 1997, The MAD-related protein Smad7 associates with the TGFβ receptor and functions as an antagonist of TGFβ signaling. Cell 89: 1165-1173.

    Article  PubMed  CAS  Google Scholar 

  • He, W., Li, A.G., Wang, D., Han, S., Zheng, B., Goumans, M.-J., ten Dijke, P., and Wang, X.J., 2002, Overexpression of Smad7 results in severe pathological alterations in multiple epithelial tissues. EMBO J 21: 2580-2590.

    Article  PubMed  CAS  Google Scholar 

  • Heldin, C.-H., Miyazono, K., and ten Dijke, P., 1997, TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 390: 465-471.

    Article  PubMed  CAS  Google Scholar 

  • Imamura, T., Takase, M., Nishihara, A., Oeda, E., Hanai, J., Kawabata, M., and Miyazono, K., 1997, Smad6 inhibits signalling by the TGF-β superfamily. Nature 389: 622-626.

    Article  PubMed  CAS  Google Scholar 

  • Ishida W, Hamamoto T, Kusanagi K, Yagi K, Kawabata M, Takehara K, Sampath TK, Kato M, Miyazono K., 2000, Smad6 is a Smad1/5-induced Smad inhibitor. Characterization of bone morphogenetic protein-responsive element in the mouse Smad6 promoter. J Biol Chem 275: 6075-6079.

    Article  PubMed  CAS  Google Scholar 

  • Itoh, F., Asao, H., Sugamura, K., Heldin, C.-H., ten Dijke, P., and Itoh, S., 2001, Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. EMBO J 20: 4132-4142.

    Article  PubMed  CAS  Google Scholar 

  • Itoh, S., Landström, M., Hermansson, A., Itoh, F., Heldin, C.-H., Heldin, N.-E., and ten Dijke, P., 1998, Transforming growth factor β1 induces nuclear export of inhibitory Smad7. J Biol Chem 273: 29195-29201.

    Article  PubMed  CAS  Google Scholar 

  • Javelaud, D., Delmas, V., Moller, M., Sextius, P., Andre, J., Menashi, S., Larue, L., and Mauviel, A., 2005, Stable overexpression of Smad7 in human melanoma cells inhibits their tumorigenicity in vitro and in vivo. Oncogene 24: 7624-7629.

    Article  PubMed  CAS  Google Scholar 

  • Jenkins BJ, Grail D, Nheu T, Najdovska M, Wang B, Waring P, Inglese M, McLoughlin RM, Jones SA, Topley N, Baumann H, Judd LM, Giraud AS, Boussioutas A, Zhu HJ, Ernst M., 2005, Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-β signaling. Nat Med 11: 845-852.

    Article  PubMed  CAS  Google Scholar 

  • Jonson, T., Gorunova, L., Dawiskiba, S., Andrén-Sandberg, Å., Stenman, G., ten Dijke, P., Johansson, B., and Höglund, M., 1999, Molecular analyses of the 15q and 18q SMAD genes in pancreatic cancer. Genes, Chrom and Cancer 24: 62-71.

    Article  CAS  Google Scholar 

  • Kawate, S., Ohwada, S., Hamada, K., Koyama, T., Takenoshita, S., Morishita, Y., and Hagiwara, K., 2001, Mutational analysis of the Smad6 and Smad7 genes in hepatocellular carcinoma. Int J Mol Med 8: 49-52.

    PubMed  CAS  Google Scholar 

  • Kavsak, P., Rasmussen, R.K., Causing, C.G., Bonni, S., Zhu, H., Thomsen, G.H., and Wrana, J.L., 2000, Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation. Mol Cell 6: 1365-1375.

    Article  PubMed  CAS  Google Scholar 

  • Kleeff, J., Ishiwata, T., Maruyama, H., Friess, H., Truong, P., Büchler, M.W., Falb, D., and Korc, M., 1999, The TGF-β signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene 18: 5363-5372.

    Article  PubMed  CAS  Google Scholar 

  • Koinuma, D., Shinozaki, M., Komuro, A., Goto, K., Saitoh, M., Hanyu, A., Ebina, M., Nukiwa, T., Miyazawa, K., Imamura, T., and Miyazono, K., 2003, Arkadia amplifies TGF-β superfamily signalling through degradation of Smad7. EMBO J 22: 6458-6470.

    Article  PubMed  CAS  Google Scholar 

  • Lallemand F, Mazars A, Prunier C, Bertrand F, Kornprost M, Gallea S, Roman-Roman S, Cherqui G, Atfi A. 2001, Smad7 inhibits the survival nuclear factor κB and potentiates apoptosis in epithelial cells. Oncogene 20: 879-884.

    Article  PubMed  CAS  Google Scholar 

  • Lallemand F, Seo SR, Ferrand N, Pessah M, L’Hoste S, Rawadi G, Roman-Roman S, Camonis J, Atfi A., 2005, AIP4 restricts transforming growth factor-β signaling through a ubiquitination-independent mechanism. J Biol Chem 280: 27645-27653.

    Article  PubMed  CAS  Google Scholar 

  • Lan, H.Y., Mu, W., Tomita, N., Huang, X.R., Li, J.H., Zhu, H.J., Morishita, R., and Johnson, R.J., 2003, Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model. J Am Soc Nephrol 14: 1535-1548.

    Article  PubMed  CAS  Google Scholar 

  • Landström, M., Heldin, N.-E., Bu, S., Hermansson, A., Itoh, S., ten Dijke, P., and Heldin, C.-H., 2000, Smad7 mediates apoptosis induced by transforming growth factor β in prostatic carcinoma cells. Curr Biol 10: 535-538.

    Article  PubMed  Google Scholar 

  • Leask, A., and Abraham, D.J., 2004, TGF-β signaling and the fibrotic response. FASEB J 18: 816-827.

    Article  PubMed  CAS  Google Scholar 

  • Lin, X., Liang, Y.Y., Sun, B., Liang, M., Shi, Y., Brunicardi, F.C., and Feng, X.H., 2003, Smad6 recruits transcription corepressor CtBP to repress bone morphogenetic protein-induced transcription. Mol Cell Biol 23: 9081-9093.

    Article  PubMed  CAS  Google Scholar 

  • Liu X, Lee J, Cooley M, Bhogte E, Hartley S, Glick A., 2003, Smad7 but not Smad6 cooperates with oncogenic ras to cause malignant conversion in a mouse model for squamous cell carcinoma. Cancer Res 63: 7760-7768.

    PubMed  Google Scholar 

  • Mallawaarachchi CM, Weissberg PL, Siow RC., 2005, Smad7 gene transfer attenuates adventitial cell migration and vascular remodeling after balloon injury. Arterioscler Thromb Vasc Biol 25: 1383-1387.

    Article  PubMed  CAS  Google Scholar 

  • Mazars A, Lallemand F, Prunier C, Marais J, Ferrand N, Pessah M, Cherqui G, Atfi A. 2001, Evidence for a role of the JNK cascade in Smad7-mediated apoptosis. J Biol Chem. 276: 36797-36803.

    Article  PubMed  CAS  Google Scholar 

  • Miyazono, K., 2002, A new partner for inhibitory Smads. Cytokine Growth Factor Rev 13: 7-9.

    Article  PubMed  CAS  Google Scholar 

  • Mochizuki, T., Miyazaki, H., Hara, T., Furuya, T., Imamura, T., Watabe, T., and Miyazono, K., 2004, Roles for the MH2 domain of Smad7 in the specific inhibition of transforming growth factor-β superfamily signaling. J Biol Chem 279: 31568-31574.

    Article  PubMed  CAS  Google Scholar 

  • Monteleone, G., Del Vecchio Blanco, G., Palmieri, G., Vavassori, P., Monteleone, I., Colantoni, A., Battista, S., Spagnoli, L.G., Romano, M., Borrelli, M., MacDonald, T.T., and Pallone, F., 2004, Induction and regulation of Smad7 in the gastric mucosa of patients with Helicobacter pylori infection. Gastroenterology 126: 674-682.

    Article  PubMed  CAS  Google Scholar 

  • Monteleone, G., Kumberova, A., Croft, N.M., McKenzie, C., Steer, H.W., and MacDonald, T.T., 2001, Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease. J Clin Invest 108: 601-609.

    Article  PubMed  CAS  Google Scholar 

  • Nagarajan, R.P., Zhang, J., Li, W., and Chen, Y., 1999, Regulation of Smad7 promoter by direct association with Smad3 and Smad4. J Biol Chem 274: 33412-33418.

    Article  PubMed  CAS  Google Scholar 

  • Nakao, A., Afrakhte, M., Morén, A., Nakayama, T., Christian, J.L., Heuchel, R., Itoh, S., Kawabata, M., Heldin, N.-E., Heldin, C.-H., and ten Dijke, P., 1997, Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature 389: 631-635.

    Article  PubMed  CAS  Google Scholar 

  • Nakao, A., Fujii, M., Matsumura, R., Kumano, K., Saito, Y., Miyazono, K., and Iwamoto, I., 1999, Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. J Clin Invest 104: 5-11.

    Article  PubMed  CAS  Google Scholar 

  • Nakao, A., Okumura, K., and Ogawa, H., 2002a, Smad7: a new key player in TGF-β-associated disease. Trends Mol Med 8: 361-363.

    Article  CAS  Google Scholar 

  • Nakao, A., Sagara, H., Setoguchi, Y., Okada, T., Okumura, K., Ogawa, H., and Fukuda, T., 2002b, Expression of Smad7 in bronchial epithelial cells is inversely correlated to basement membrane thickness and airway hyperresponsiveness in patients with asthma. J Allergy Clin Immunol 110: 873-878.

    Article  CAS  Google Scholar 

  • Nakayama, T., Gardner, H., Berg, L.K., and Christian, J.L., 1998a, Smad6 functions as an intracellular antagonist of some TGF-β family members during Xenopus embryogenesis. Genes Cells 3: 387-394.

    Article  CAS  Google Scholar 

  • Nakayama, T., Snyder, M.A., Grewal, S.S., Tsuneizumi, K., Tabata, T., and Christian, J.L., 1998b, Xenopus Smad8 acts downstream of BMP-4 to modulate its activity during vertebrate embryonic patterning. Development 125: 857-867.

    CAS  Google Scholar 

  • Quan T, He T, Voorhees JJ, Fisher GJ., 2005, Ultraviolet irradiation induces Smad7 via induction of transcription factor AP-1 in human skin fibroblasts. J Biol Chem 280: 8079-8085.

    Article  PubMed  CAS  Google Scholar 

  • Riggins, R.G., Kinzler, K.W., Vogelstein, B., and Thiagalingam, S., 1997, Frequency of Smad gene mutations in human cancers. Cancer Res 57: 2578-2580.

    PubMed  CAS  Google Scholar 

  • Roberts, A.B., and Wakefield, L.M., 2003, The two faces of transforming growth factor β in carcinogenesis. Proc Natl Acad Sci U S A 100: 8621-8623.

    Article  PubMed  CAS  Google Scholar 

  • Schiffer, M., Bitzer, M., Roberts, I.S., Kopp, J.B., ten Dijke, P., Mundel, P., and Böttinger, E.P., 2001, Apoptosis in podocytes induced by TGF-β and Smad7. J Clin Invest 108: 807-816.

    Article  PubMed  CAS  Google Scholar 

  • Shi, W., Sun, C., He, B., Xiong, W., Shi, X., Yao, D., and Cao, X., 2004, GADD34-PP1c recruited by Smad7 dephosphorylates TGFβ type I receptor. J Cell Biol 164: 291-300.

    Article  PubMed  CAS  Google Scholar 

  • Souchelnytskyi, S., Nakayama, T., Nakao, A., Morén, A., Heldin, C.-H., Christian, J.L., and ten Dijke, P., 1998, Physical and functional interaction of murine and Xenopus Smad7 with bone morphogenetic protein receptors and transforming growth factor-β receptors. J Biol Chem 273: 25364-25370.

    Article  PubMed  CAS  Google Scholar 

  • Strober, W., Kelsall, B., Fuss, I., Marth, T., Ludviksson, B., Ehrhardt, R., and Neurath, M., 1997, Reciprocal IFN-γ and TGF-β responses regulate the occurrence of mucosal inflammation. Immunol Today 18: 61-64.

    Article  PubMed  CAS  Google Scholar 

  • Takase, M., Imamura, T., Sampath, T.K., Takeda, K., Ichijo, H., Miyazono, K., and Kawabata, M., 1998, Induction of Smad6 mRNA by bone morphogenetic proteins. Biochem Biophys Res Commun 244: 26-29.

    Article  PubMed  CAS  Google Scholar 

  • Topper, J.N., Cai, J., Qiu, Y., Anderson, K.R., Xu, Y.-Y., Deeds, J.D., Feeley, R., Gimeno, C.J., Woolf, E.A., Tayber, O., Mays, G.G., Sampson, B.A., Schoen, F.J., Gimbrone Jr., M.A., and Falb, D., 1997, Vascular MADs: Two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Proc Natl Acad Sci U S A 94: 9314-9319.

    Article  PubMed  CAS  Google Scholar 

  • Torregroza, I., and Evans, T., 2006, Tid1 is a Smad-binding protein that can modulate Smad7 activity in developing embryos. Biochem J 393: 311-320.

    Article  PubMed  CAS  Google Scholar 

  • Tsuneizumi, K., Nakayama, T., Kamoshida, Y., Kornberg, T.B., Christian, J.L., and Tabata, T., 1997, Daughters against dpp modulates dpp organizing activity in Drosophila wing development. Nature 389: 627-631.

    Article  PubMed  CAS  Google Scholar 

  • Ulloa, L., Doody, J., and Massagué, J., 1999, Inhibition of transforming growth factor-β/SMAD signalling by the interferon-gamma/STAT pathway. Nature 397: 710-713.

    Article  PubMed  CAS  Google Scholar 

  • Yoshimura, A., Mori, H., Ohishi, M., Aki, D., and Hanada, T., 2003, Negative regulation of cytokine signaling influences inflammation. Curr Opin Immunol 15: 704-708.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan

    Atsuhito Nakao

  2. Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo 113-8421, Japan

    Atsuhito Nakao

Authors
  1. Atsuhito Nakao
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Leiden University Medical Center, Leiden, The Netherlands

    Peter ten Dijke

  2. Ludwig Institute for Cancer Research, Uppsala University, Sweden

    Carl-Henrik Heldin

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Springer

About this chapter

Cite this chapter

Nakao, A. (2006). Inhibitory Smads: Mechanisms of Action and Roles in Human Diseases. In: Dijke, P.t., Heldin, CH. (eds) Smad Signal Transduction. Proteins and Cell Regulation, vol 5. Springer, Dordrecht. https://doi.org/10.1007/1-4020-4709-6_19

Download citation

Publish with us

Policies and ethics

Search

Navigation