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Bone morphogenetic protein signaling is fine-tuned on multiple levels

  • Christina Sieber
  • Gerburg K. Schwaerzer
  • Petra Knaus
Part of the Progress in Inflammation Research book series (PIR)

Abstract

The receptors for ligands of the bone morphogenetic protein (BMP) family translate signals from the outside to the inside of the cell. In the cytoplasm, stimuli are received by signal transducer molecules. This process passes through numerous stages and checkpoints, which are depicted in the following paragraphs.

Keywords

Responsive Genes Bone Morphogenetic Protein Signaling Signal Transducer Molecule Receptor Associate Protein 3MAD Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Shimasaki S, Moore RK, Otsuka F, Erickson GF (2004) The bone morphogenetic protein system in mammalian reproduction. Endocr Rev 25: 72–101CrossRefGoogle Scholar
  2. 2.
    Molloy SS, Bresnahan PA, Leppla SH, Klimpel KR, Thomas G (1992) Human furin is a calcium-dependent serine endoprotease that recognizes the sequence Arg-X-X-Arg and efficiently cleaves anthrax toxin protective antigen. J Biol Chem 267: 16396–16402Google Scholar
  3. 3.
    Schlunegger MP, Grutter MG (1992) An unusual feature revealed by the crystal structure at 2.2 Å resolution of human transforming growth factor-beta 2. Nature 358: 430–434CrossRefGoogle Scholar
  4. 4.
    Kingsley DM (1994) The TGF-beta superfamily: New members, new receptors, and new genetic tests of function in different organisms. Genes Dev 8: 133–146CrossRefGoogle Scholar
  5. 5.
    McPherron AC, Lee SJ (1993) GDF-3 and GDF-9: Two new members of the transforming growth factor-beta superfamily containing a novel pattern of cysteines. J Biol Chem 268: 3444–3449Google Scholar
  6. 6.
    Liao WX, Moore RK, Otsuka F, Shimasaki S (2003) Effect of intracellular interactions on the processing and secretion of bone morphogenetic protein-15 (BMP-15) and growth and differentiation factor-9. Implication of the aberrant ovarian phenotype of BMP-15 mutant sheep. J Biol Chem 278: 3713–3719CrossRefGoogle Scholar
  7. 7.
    Sieber C, Ploger F, Schwappacher R, Bechtold R, Hanke M, Kawai S, Muraki Y, Katsuura M, Kimura M, Rechtman MM et al (2006) Monomeric and dimeric GDF-5 show equal type I receptor binding and oligomerization capability and have the same biological activity. Biol Chem 387: 451–460CrossRefGoogle Scholar
  8. 8.
    Israel DI, Nove J, Kerns KM, Kaufman RJ, Rosen V, Cox KA, Wozney JM (1996) Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo. Growth Factors 13: 291–300CrossRefGoogle Scholar
  9. 9.
    Scheufler C, Sebald W, Hulsmeyer M (1999) Crystal structure of human bone morphogenetic protein-2 at 2.7 Å resolution. J Mol Biol 287: 103–115CrossRefGoogle Scholar
  10. 10.
    Griffith DL, Keck PC, Sampath TK, Rueger DC, Carlson WD (1996) Three-dimensional structure of recombinant human osteogenic protein 1: Structural paradigm for the transforming growth factor beta superfamily. Proc Natl Acad Sci USA 93: 878–883CrossRefGoogle Scholar
  11. 11.
    Greenwald J, Groppe J, Gray P, Wiater E, Kwiatkowski W, Vale W, Choe S (2003) The BMP-7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Mol Cell 11: 605–617CrossRefGoogle Scholar
  12. 12.
    Brown MA, Zhao Q, Baker KA, Naik C, Chen C, Pukac L, Singh M, Tsareva T, Parice Y, Mahoney A et al (2005) Crystal structure of BMP-9 and functional interactions with pro-region and receptors. J Biol Chem 280: 25111–25118CrossRefGoogle Scholar
  13. 13.
    Schreuder H, Liesum A, Pohl J, Kruse M, Koyama M (2005) Crystal structure of recombinant human growth and differentiation factor 5: Evidence for interaction of the type I and type II receptor-binding sites. Biochem Biophys Res Commun 329: 1076–1086CrossRefGoogle Scholar
  14. 14.
    Lin SJ, Lerch TF, Cook RW, Jardetzky TS, Woodruff TK (2006) The structural basis of TGF-beta, bone morphogenetic protein, and activin ligand binding. Reproduction 132: 179–190CrossRefGoogle Scholar
  15. 15.
    Lehmann K, Seemann P, Boergermann J, Morin G, Reif S, Knaus P, Mundlos S (2006) A novel R486Q mutation in BMPR1B resulting in either a brachydactyly type C/symphalangism-like phenotype or brachydactyly type A2. Eur J Hum Genet 14: 1248–1254CrossRefGoogle Scholar
  16. 16.
    Kjaer KW, Eiberg H, Hansen L, van der Hagen CB, Rosendahl K, Tommerup N, Mundlos S (2006) A mutation in the receptor binding site of GDF-5 causes Mohr-Wriedt brachydactyly type A2. J Med Genet 43: 225–231CrossRefGoogle Scholar
  17. 17.
    Lehmann K, Seemann P, Stricker S, Sammar M, Meyer B, Suring K, Majewski F, Tinschert S, Grzeschik KH, Muller D et al (2003) Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2. Proc Natl Acad Sci USA 100: 12277–12282CrossRefGoogle Scholar
  18. 18.
    Seemann P, Schwappacher R, Kjaer KW, Krakow D, Lehmann K, Dawson K, Stricker S, Pohl J, Ploger F, Staub E et al (2005) Activating and deactivating mutations in the receptor interaction site of GDF-5 cause symphalangism or brachydactyly type A2. J Clin Invest 115: 2373–2381CrossRefGoogle Scholar
  19. 19.
    Chen YG, Hata A, Lo RS, Wotton D, Shi Y, Pavletich N, Massague J (1998) Determinants of specificity in TGF-beta signal transduction. Genes Dev 12: 2144–2152CrossRefGoogle Scholar
  20. 20.
    Lo RS, Chen YG, Shi Y, Pavletich NP, Massague J (1998) The L3 loop: A structural motif determining specific interactions between SMAD proteins and TGF-beta receptors. EMBO J 17: 996–1005CrossRefGoogle Scholar
  21. 21.
    ten Dijke P, Ichijo H, Franzen P, Schulz P, Saras J, Toyoshima H, Heldin CH, Miyazono K (1993) Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. Oncogene 8: 2879–2887Google Scholar
  22. 22.
    ten Dijke P, Yamashita H, Sampath TK, Reddi AH, Estevez M, Riddle DL, Ichijo H, Heldin CH, Miyazono K (1994) Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem 269: 16985–16988Google Scholar
  23. 23.
    Zimmerman CM, Mathews LS (1996) Activin receptors: Cellular signalling by receptor serine kinases. Biochem Soc Symp 62: 25–38Google Scholar
  24. 24.
    Zou H, Wieser R, Massague J, Niswander L (1997) Distinct roles of type I bone morphogenetic protein receptors in the formation and differentiation of cartilage. Genes Dev 11: 2191–2203CrossRefGoogle Scholar
  25. 25.
    Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, Petersen GM, Velculescu VE, Traverso G, Vogelstein B (2001) Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 28: 184–187CrossRefGoogle Scholar
  26. 26.
    Sayed MG, Ahmed AF, Ringold JR, Anderson ME, Bair JL, Mitros FA, Lynch HT, Tinley ST, Petersen GM, Giardiello FM et al (2002) Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. Ann Surg Oncol 9: 901–906CrossRefGoogle Scholar
  27. 27.
    Virdi AS, Shore EM, Oreffo RO, Li M, Connor JM, Smith R, Kaplan FS, Triffitt JT (1999) Phenotypic and molecular heterogeneity in fibrodysplasia ossificans progressiva. Calcif Tissue Int 65: 250–255CrossRefGoogle Scholar
  28. 28.
    Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M et al (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38: 525–527CrossRefGoogle Scholar
  29. 29.
    Kawabata M, Chytil A, Moses HL (1995) Cloning of a novel type II serine/threonine kinase receptor through interaction with the type I transforming growth factor-beta receptor. J Biol Chem 270: 5625–5630CrossRefGoogle Scholar
  30. 30.
    Rosenzweig BL, Imamura T, Okadome T, Cox GN, Yamashita H, ten Dijke P, Heldin CH, Miyazono K (1995) Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci USA 92: 7632–7636CrossRefGoogle Scholar
  31. 31.
    Liu F, Ventura F, Doody J, Massague J (1995) Human type II receptor for bone morphogenic proteins (BMPs): Extension of the two-kinase receptor model to the BMPs. Mol Cell Biol 15: 3479–3486Google Scholar
  32. 32.
    Nohno T, Ishikawa T, Saito T, Hosokawa K, Noji S, Wolsing DH, Rosenbaum JS (1995) Identification of a human type II receptor for bone morphogenetic protein-4 that forms differential heteromeric complexes with bone morphogenetic protein type I receptors. J Biol Chem 270: 22522–22526CrossRefGoogle Scholar
  33. 33.
    Hassel S, Eichner A, Yakymovych M, Hellman U, Knaus P, Souchelnytskyi S (2004) Proteins associated with type II bone morphogenetic protein receptor (BMPR-II) and identified by two-dimensional gel electrophoresis and mass spectrometry. Proteomics 4: 1346–1358CrossRefGoogle Scholar
  34. 34.
    Morrell NW (2006) Pulmonary hypertension due to BMPR2 mutation: A new paradigm for tissue remodeling? Proc Am Thorac Soc 3: 680–686CrossRefGoogle Scholar
  35. 35.
    Liu D, Wang J, Kinzel B, Mueller M, Mao X, Valdez R, Liu Y, Li E (2007) Dosagedependent requirement of BMP type II receptor for maintenance of vascular integrity. Blood 110: 1502–1510CrossRefGoogle Scholar
  36. 36.
    Zakrzewicz A, Hecker M, Marsh LM, Kwapiszewska G, Nejman B, Long L, Seeger W, Schermuly RT, Morrell NW, Morty RE et al (2007) Receptor for activated C-kinase 1, a novel interaction partner of type II bone morphogenetic protein receptor, regulates smooth muscle cell proliferation in pulmonary arterial hypertension. Circulation 115: 2957–2968CrossRefGoogle Scholar
  37. 37.
    Kirsch T, Sebald W, Dreyer MK (2000) Crystal structure of the BMP-2-BRIA ectodomain complex. Nat Struct Biol 7: 492–496CrossRefGoogle Scholar
  38. 38.
    Kirsch T, Nickel J, Sebald W (2000) Isolation of recombinant BMP receptor IA ectodomain and its 2:1 complex with BMP-2. FEBS Lett 468: 215–219CrossRefGoogle Scholar
  39. 39.
    Allendorph GP, Vale WW, Choe S (2006) Structure of the ternary signaling complex of a TGF-beta superfamily member. Proc Natl Acad Sci USA 103: 7643–7648CrossRefGoogle Scholar
  40. 40.
    Weber D, Kotzsch A, Nickel J, Harth S, Seher A, Mueller U, Sebald W, Mueller TD (2007) A silent H-bond can be mutationally activated for high-affinity interaction of BMP-2 and activin type IIB receptor. BMC Struct Biol 7: 6CrossRefGoogle Scholar
  41. 41.
    Gray PC, Greenwald J, Blount AL, Kunitake KS, Donaldson CJ, Choe S, Vale W (2000) Identification of a binding site on the type II activin receptor for activin and inhibin. J Biol Chem 275: 3206–3212CrossRefGoogle Scholar
  42. 42.
    Knaus P, Sebald W (2001) Cooperativity of binding epitopes and receptor chains in the BMP/TGFbeta superfamily. Biol Chem 382: 1189–1195CrossRefGoogle Scholar
  43. 43.
    Mitchell H, Choudhury A, Pagano RE, Leof EB (2004) Ligand-dependent and-independent transforming growth factor-beta receptor recycling regulated by clathrin-mediated endocytosis and Rab11. Mol Biol Cell 15: 4166–4178CrossRefGoogle Scholar
  44. 44.
    Di Guglielmo GM, Le Roy C, Goodfellow AF, Wrana JL (2003) Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol 5: 410–421CrossRefGoogle Scholar
  45. 45.
    Gilboa L, Nohe A, Geissendorfer T, Sebald W, Henis YI, Knaus P (2000) Bone morphogenetic protein receptor complexes on the surface of live cells: A new oligomerization mode for serine/threonine kinase receptors. Mol Biol Cell 11: 1023–1035Google Scholar
  46. 46.
    Nohe A, Hassel S, Ehrlich M, Neubauer F, Sebald W, Henis YI, Knaus P (2002) The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J Biol Chem 277: 5330–5338CrossRefGoogle Scholar
  47. 47.
    Hartung A, Bitton-Worms K, Rechtman MM, Wenzel V, Boergermann JH, Hassel S, Henis YI, Knaus P (2006) Different routes of bone morphogenic protein (BMP) receptor endocytosis influence BMP signaling. Mol Cell Biol 26: 7791–805CrossRefGoogle Scholar
  48. 48.
    Zhang Y, Feng X, We R, Derynck R (1996) Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature 383: 168–172CrossRefGoogle Scholar
  49. 49.
    Wrana JL, Attisano L, Wieser R, Ventura F, Massague J (1994) Mechanism of activation of the TGF-beta receptor. Nature 370: 341–347CrossRefGoogle Scholar
  50. 50.
    Shi W, Chang C, Nie S, Xie S, Wan M, Cao X (2007) Endofin acts as a Smad anchor for receptor activation in BMP signaling. J Cell Sci 120: 1216–1224CrossRefGoogle Scholar
  51. 51.
    Kretzschmar M, Doody J, Massague J (1997) Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature 389: 618–622CrossRefGoogle Scholar
  52. 52.
    Korchynskyi O, ten Dijke P (2002) Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter. J Biol Chem 277: 4883–4891CrossRefGoogle Scholar
  53. 53.
    Kusanagi K, Inoue H, Ishidou Y, Mishima HK, Kawabata M, Miyazono K (2000) Characterization of a bone morphogenetic protein-responsive Smad-binding element. Mol Biol Cell 11: 555–565Google Scholar
  54. 54.
    Korchynskyi O, Dechering KJ, Sijbers AM, Olijve W, ten Dijke P (2003) Gene array analysis of bone morphogenetic protein type I receptor-induced osteoblast differentiation. J Bone Miner Res 18: 1177–1185CrossRefGoogle Scholar
  55. 55.
    de Jong DS, Vaes BL, Dechering KJ, Feijen A, Hendriks JM, Wehrens R, Mummery CL, van Zoelen EJ, Olijve W, Steegenga WT (2004) Identification of novel regulators associated with early-phase osteoblast differentiation. J Bone Miner Res 19: 947–958CrossRefGoogle Scholar
  56. 56.
    Knockaert M, Sapkota G, Alarcon C, Massague J, Brivanlou AH (2006) Unique players in the BMP pathway: Small C-terminal domain phosphatases dephosphorylate Smad1 to attenuate BMP signaling. Proc Natl Acad Sci USA 103: 11940–11945CrossRefGoogle Scholar
  57. 57.
    Chen HB, Shen J, Ip YT, Xu L (2006) Identification of phosphatases for Smad in the BMP/DPP pathway. Genes Dev 20: 648–653CrossRefGoogle Scholar
  58. 58.
    Duan X, Liang YY, Feng XH, Lin X (2006) Protein serine/threonine phosphatase PPM1A dephosphorylates Smad1 in the bone morphogenetic protein signaling pathway. J Biol Chem 281: 36526–36532CrossRefGoogle Scholar
  59. 59.
    Sapkota G, Knockaert M, Alarcon C, Montalvo E, Brivanlou AH, Massague J (2006) Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-beta pathways. J Biol Chem 281: 40412–40419CrossRefGoogle Scholar
  60. 60.
    Hata A, Lagna G, Massague J, Hemmati-Brivanlou A (1998) Smad6 inhibits BMP/ Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 12: 186–197CrossRefGoogle Scholar
  61. 61.
    Bennett D, Alphey L (2002) PP1 binds Sara and negatively regulates Dpp signaling in Drosophila melanogaster. Nat Genet 31: 419–423Google Scholar
  62. 62.
    Murakami G, Watabe T, Takaoka K, Miyazono K, Imamura T (2003) Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Mol Biol Cell 14: 2809–2817CrossRefGoogle Scholar
  63. 63.
    Zhang Y, Chang C, Gehling DJ, Hemmati-Brivanlou A, Derynck R (2001) Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci USA 98: 974–979CrossRefGoogle Scholar
  64. 64.
    Zhu H, Kavsak P, Abdollah S, Wrana JL, Thomsen GH (1999) A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400: 687–693CrossRefGoogle Scholar
  65. 65.
    Shen R, Chen M, Wang YJ, Kaneki H, Xing L, O’Keefe RJ, Chen D (2006) Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation. J Biol Chem 281: 3569–3576CrossRefGoogle Scholar
  66. 66.
    Kim BC, Lee HJ, Park SH, Lee SR, Karpova TS, McNally JG, Felici A, Lee DK, Kim SJ (2004) Jab1/CSN5, a component of the COP9 signalosome, regulates transforming growth factor beta signaling by binding to Smad7 and promoting its degradation. Mol Cell Biol 24: 2251–2262CrossRefGoogle Scholar
  67. 67.
    Komuro A, Imamura T, Saitoh M, Yoshida Y, Yamori T, Miyazono K, Miyazawa K (2004) Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1). Oncogene 23: 6914–6923CrossRefGoogle Scholar
  68. 68.
    Lin X, Liang M, Liang YY, Brunicardi FC, Feng XH (2003) SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor Smad4. J Biol Chem 278: 31043–31048CrossRefGoogle Scholar
  69. 69.
    Lee PS, Chang C, Liu D, Derynck R (2003) Sumoylation of Smad4, the common Smad mediator of transforming growth factor-beta family signaling. J Biol Chem 278: 27853–27863CrossRefGoogle Scholar
  70. 70.
    Li L, Xin H, Xu X, Huang M, Zhang X, Chen Y, Zhang S, Fu XY, Chang Z (2004) CHIP mediates degradation of Smad proteins and potentially regulates Smad-induced transcription. Mol Cell Biol 24: 856–864CrossRefGoogle Scholar
  71. 71.
    Wan M, Tang Y, Tytler EM, Lu C, Jin B, Vickers SM, Yang L, Shi X, Cao X (2004) Smad4 protein stability is regulated by ubiquitin ligase SCF beta-TrCP1. J Biol Chem 279: 14484–14487CrossRefGoogle Scholar
  72. 72.
    Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S (2001) Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. EMBO J 20: 4132–4142CrossRefGoogle Scholar
  73. 73.
    Nohe A, Keating E, Knaus P, Petersen NO (2004) Signal transduction of bone morphogenetic protein receptors. Cell Signal 16: 291–299CrossRefGoogle Scholar
  74. 74.
    Lu M, Lin SC, Huang Y, Kang YJ, Rich R, Lo YC, Myszka D, Han J, Wu H (2007) XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization. Mol Cell 26: 689–702CrossRefGoogle Scholar
  75. 75.
    Chai J, Shiozaki E, Srinivasula SM, Wu Q, Datta P, Alnemri ES, Shi Y (2001) Structural basis of caspase-7 inhibition by XIAP. Cell 104: 769–780CrossRefGoogle Scholar
  76. 76.
    Huang Y, Park YC, Rich RL, Segal D, Myszka DG, Wu H (2001) Structural basis of caspase inhibition by XIAP: Differential roles of the linker versus the BIR domain. Cell 104: 781–790Google Scholar
  77. 77.
    Riedl SJ, Renatus M, Schwarzenbacher R, Zhou Q, Sun C, Fesik SW, Liddington RC, Salvesen GS (2001) Structural basis for the inhibition of caspase-3 by XIAP. Cell 104: 791–800CrossRefGoogle Scholar
  78. 78.
    Shiozaki EN, Chai J, Rigotti DJ, Riedl SJ, Li P, Srinivasula SM, Alnemri ES, Fairman R, Shi Y (2003) Mechanism of XIAP-mediated inhibition of caspase-9. Mol Cell 11: 519–527CrossRefGoogle Scholar
  79. 79.
    Shibuya H, Yamaguchi K, Shirakabe K, Tonegawa A, Gotoh Y, Ueno N, Irie K, Nishida E, Matsumoto K (1996) TAB1: An activator of the TAK1 MAPKKK in TGF-beta signal transduction. Science 272: 1179–1182CrossRefGoogle Scholar
  80. 80.
    Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ (2001) TAK1 is a ubiquitindependent kinase of MKK and IKK. Nature 412: 346–351CrossRefGoogle Scholar
  81. 81.
    Shirakabe K, Yamaguchi K, Shibuya H, Irie K, Matsuda S, Moriguchi T, Gotoh Y, Matsumoto K, Nishida E (1997) TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. J Biol Chem 272: 8141–8144CrossRefGoogle Scholar
  82. 82.
    Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K, Ueno N, Nishida E, Shibuya H, Matsumoto K (1999) XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. EMBO J 18: 179–187CrossRefGoogle Scholar
  83. 83.
    Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, Ueno N, Taniguchi T, Nishida E, Matsumoto K (1995) Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 270: 2008–2011CrossRefGoogle Scholar
  84. 84.
    Lewis J, Burstein E, Reffey SB, Bratton SB, Roberts AB, Duckett CS (2004) Uncoupling of the signaling and caspase-inhibitory properties of X-linked inhibitor of apoptosis. J Biol Chem 279: 9023–9029CrossRefGoogle Scholar
  85. 85.
    Sanna MG, Duckett CS, Richter BW, Thompson CB, Ulevitch RJ (1998) Selective activation of JNK1 is necessary for the anti-apoptotic activity of hILP. Proc Natl Acad Sci USA 95: 6015–6020CrossRefGoogle Scholar
  86. 86.
    Shibuya H, Iwata H, Masuyama N, Gotoh Y, Yamaguchi K, Irie K, Matsumoto K, Nishida E, Ueno N (1998) Role of TAK1 and TAB1 in BMP signaling in early Xenopus development. EMBO J 17: 1019–1028CrossRefGoogle Scholar
  87. 87.
    Sano Y, Harada J, Tashiro S, Gotoh-Mandeville R, Maekawa T, Ishii S (1999) ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factorbeta signaling. J Biol Chem 274: 8949–8957CrossRefGoogle Scholar
  88. 88.
    Lai CF, Cheng SL (2002) Signal transductions induced by bone morphogenetic protein-2 and transforming growth factor-beta in normal human osteoblastic cells. J Biol Chem 277: 15514–15522CrossRefGoogle Scholar
  89. 89.
    Gallea S, Lallemand F, Atfi A, Rawadi G, Ramez V, Spinella-Jaegle S, Kawai S, Faucheu C, Huet L, Baron R et al (2001) Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells. Bone 28: 491–498CrossRefGoogle Scholar
  90. 90.
    Guicheux J, Lemonnier J, Ghayor C, Suzuki A, Palmer G, Caverzasio J (2003) Activation of p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase by BMP-2 and their implication in the stimulation of osteoblastic cell differentiation. J Bone Miner Res 18: 2060–2068CrossRefGoogle Scholar
  91. 91.
    Zuzarte-Luis V, Montero JA, Rodriguez-Leon J, Merino R, Rodriguez-Rey JC, Hurle JM (2004) A new role for BMP5 during limb development acting through the synergic activation of Smad and MAPK pathways. Dev Biol 272: 39–52CrossRefGoogle Scholar
  92. 92.
    Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T (2000) BMP-2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem 275: 17647–17652CrossRefGoogle Scholar
  93. 93.
    Edlund S, Bu S, Schuster N, Aspenstrom P, Heuchel R, Heldin NE, ten Dijke P, Heldin CH, Landstrom M (2003) Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGFbeta-activated kinase 1 and mitogen-activated protein kinase kinase 3. Mol Biol Cell 14: 529–544CrossRefGoogle Scholar
  94. 94.
    Ghosh-Choudhury N, Abboud SL, Nishimura R, Celeste A, Mahimainathan L, Choudhury GG (2002) Requirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and Smad-dependent BMP-2 gene transcription. J Biol Chem 277: 33361–33368CrossRefGoogle Scholar
  95. 95.
    Vinals F, Lopez-Rovira T, Rosa JL, Ventura F (2002) Inhibition of PI3K/p70 S6K and p38 MAPK cascades increases osteoblastic differentiation induced by BMP-2. FEBS Lett 510: 99–104CrossRefGoogle Scholar
  96. 96.
    Osyczka AM, Leboy PS (2005) Bone morphogenetic protein regulation of early osteoblast genes in human marrow stromal cells is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling. Endocrinology 146: 3428–3437CrossRefGoogle Scholar
  97. 97.
    Manning BD, Cantley LC (2007) AKT/PKB signaling: Navigating downstream. Cell 129: 1261–1274CrossRefGoogle Scholar
  98. 98.
    Kobielak K, Stokes N, de la Cruz J, Polak L, Fuchs E (2007) Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling. Proc Natl Acad Sci USA 104: 10063–10068CrossRefGoogle Scholar
  99. 99.
    Palcy S, Bolivar I, Goltzman D (2000) Role of activator protein 1 transcriptional activity in the regulation of gene expression by transforming growth factor beta1 and bone morphogenetic protein 2 in ROS 17/2.8 osteoblast-like cells. J Bone Miner Res 15: 2352–2361CrossRefGoogle Scholar
  100. 100.
    Wong WK, Knowles JA, Morse JH (2005) Bone morphogenetic protein receptor type II C-terminus interacts with c-Src: Implication for a role in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 33: 438–446CrossRefGoogle Scholar
  101. 101.
    Machado RD, Rudarakanchana N, Atkinson C, Flanagan JA, Harrison R, Morrell NW, Trembath RC (2003) Functional interaction between BMPR-II and Tctex-1, a light chain of Dynein, is isoform-specific and disrupted by mutations underlying primary pulmonary hypertension. Hum Mol Genet 12: 3277–3286CrossRefGoogle Scholar
  102. 102.
    Foletta VC, Moussi N, Sarmiere PD, Bamburg JR, Bernard O (2004) LIM kinase 1, a key regulator of actin dynamics, is widely expressed in embryonic and adult tissues. Exp Cell Res 294: 392–405CrossRefGoogle Scholar
  103. 103.
    Lee-Hoeflich ST, Causing CG, Podkowa M, Zhao X, Wrana JL, Attisano L (2004) Activation of LIMK1 by binding to the BMP receptor, BMPRII, regulates BMP-dependent dendritogenesis. EMBO J 23: 4792–4801CrossRefGoogle Scholar
  104. 104.
    Yanagita M (2005) BMP antagonists: their roles in development and involvement in pathophysiology. Cytokine Growth Factor Rev 16: 309–317CrossRefGoogle Scholar
  105. 105.
    Gazzerro E, Canalis E (2006) Bone morphogenetic proteins and their antagonists. Rev Endocr Metab Disord 7: 51–65CrossRefGoogle Scholar
  106. 106.
    van Bezooijen RL, ten Dijke P, Papapoulos SE, Lowik CW (2005) SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine Growth Factor Rev 16: 319–327CrossRefGoogle Scholar
  107. 107.
    Tamaoki H, Miura R, Kusunoki M, Kyogoku Y, Kobayashi Y, Moroder L (1998) Folding motifs induced and stabilized by distinct cystine frameworks. Protein Eng 11: 649–659CrossRefGoogle Scholar
  108. 108.
    Vitt UA, Hsu SY, Hsueh AJ (2001) Evolution and classification of cystine knot-containing hormones and related extracellular signaling molecules. Mol Endocrinol 15: 681–694CrossRefGoogle Scholar
  109. 109.
    Avsian-Kretchmer O, Hsueh AJ (2004) Comparative genomic analysis of the eightmembered ring cystine knot-containing bone morphogenetic protein antagonists. Mol Endocrinol 18: 1–12CrossRefGoogle Scholar
  110. 110.
    Ozaki T, Sakiyama S (1993) Molecular cloning of rat calpactin I heavy-chain cDNA whose expression is induced in v-src-transformed rat culture cell lines. Oncogene 8: 1707–1710Google Scholar
  111. 111.
    Ozaki T, Sakiyama S (1994) Tumor-suppressive activity of N03 gene product in v-srctransformed rat 3Y1 fibroblasts. Cancer Res 54: 646–648Google Scholar
  112. 112.
    Dionne MS, Skarnes WC, Harland RM (2001) Mutation and analysis of Dan, the founding member of the Dan family of transforming growth factor beta antagonists. Mol Cell Biol 21: 636–643CrossRefGoogle Scholar
  113. 113.
    Stanley E, Biben C, Kotecha S, Fabri L, Tajbakhsh S, Wang CC, Hatzistavrou T, Roberts B, Drinkwater C, Lah M et al (1998) DAN is a secreted glycoprotein related to Xenopus cerberus. Mech Dev 77: 173–184CrossRefGoogle Scholar
  114. 114.
    Bouwmeester T, Kim S, Sasai Y, Lu B, De Robertis EM (1996) Cerberus is a head-inducing secreted factor expressed in the anterior endoderm of Spemann’s organizer. Nature 382: 595–601CrossRefGoogle Scholar
  115. 115.
    Piccolo S, Agius E, Leyns L, Bhattacharyya S, Grunz H, Bouwmeester T, De Robertis EM (1999) The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature 397: 707–710CrossRefGoogle Scholar
  116. 116.
    Belo JA, Bachiller D, Agius E, Kemp C, Borges AC, Marques S, Piccolo S, De Robertis EM (2000) Cerberus-like is a secreted BMP and nodal antagonist not essential for mouse development. Genesis 26: 265–270CrossRefGoogle Scholar
  117. 117.
    Biben C, Stanley E, Fabri L, Kotecha S, Rhinn M, Drinkwater C, Lah M, Wang CC, Nash A, Hilton D et al (1998) Murine cerberus homologue mCer-1: a candidate anterior patterning molecule. Dev Biol 194: 135–151CrossRefGoogle Scholar
  118. 118.
    Shawlot W, Min Deng J, Wakamiya M, Behringer RR (2000) The cerberus-related gene, Cerr1, is not essential for mouse head formation. Genesis 26: 253–258CrossRefGoogle Scholar
  119. 119.
    Shawlot W, Deng JM, Behringer RR (1998) Expression of the mouse cerberus-related gene, Cerr1, suggests a role in anterior neural induction and somitogenesis. Proc Natl Acad Sci USA 95: 6198–6203CrossRefGoogle Scholar
  120. 120.
    Yokouchi Y, Vogan KJ, Pearse RV, 2nd, Tabin CJ (1999) Antagonistic signaling by Caronte, a novel Cerberus-related gene, establishes left-right asymmetric gene expression. Cell 98: 573–583CrossRefGoogle Scholar
  121. 121.
    Rodriguez Esteban C, Capdevila J, Economides AN, Pascual J, Ortiz A, Izpisua Belmonte JC (1999) The novel Cer-like protein Caronte mediates the establishment of embryonic left-right asymmetry. Nature 401: 243–251CrossRefGoogle Scholar
  122. 122.
    Bell E, Munoz-Sanjuan I, Altmann CR, Vonica A, Brivanlou AH (2003) Cell fate specification and competence by Coco, a maternal BMP, TGFbeta and Wnt inhibitor. Development 130: 1381–1389CrossRefGoogle Scholar
  123. 123.
    Pearce JJ, Penny G, Rossant J (1999) A mouse cerberus/Dan-related gene family. Dev Biol 209: 98–110CrossRefGoogle Scholar
  124. 124.
    Minabe-Saegusa C, Saegusa H, Tsukahara M, Noguchi S (1998) Sequence and expression of a novel mouse gene PRDC (protein related to DAN and cerberus) identified by a gene trap approach. Dev Growth Differ 40: 343–353CrossRefGoogle Scholar
  125. 125.
    Hsu DR, Economides AN, Wang X, Eimon PM, Harland RM (1998) The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP activities. Mol Cell 1: 673–683CrossRefGoogle Scholar
  126. 126.
    McMahon R, Murphy M, Clarkson M, Taal M, Mackenzie HS, Godson C, Martin F, Brady HR (2000) IHG-2, a mesangial cell gene induced by high glucose, is human gremlin. Regulation by extracellular glucose concentration, cyclic mechanical strain, and transforming growth factor-beta1. J Biol Chem 275: 9901–9904CrossRefGoogle Scholar
  127. 127.
    Khokha MK, Hsu D, Brunet LJ, Dionne MS, Harland RM (2003) Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning. Nat Genet 34: 303–307CrossRefGoogle Scholar
  128. 128.
    Michos O, Goncalves A, Lopez-Rios J, Tiecke E, Naillat F, Beier K, Galli A, Vainio S, Zeller R (2007) Reduction of BMP-4 activity by gremlin 1 enables ureteric bud outgrowth and GDNF/WNT11 feedback signalling during kidney branching morphogenesis. Development 134: 2397–2405CrossRefGoogle Scholar
  129. 129.
    Michos O, Panman L, Vintersten K, Beier K, Zeller R, Zuniga A (2004) Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis. Development 131: 3401–3410CrossRefGoogle Scholar
  130. 130.
    Pereira RC, Economides AN, Canalis E (2000) Bone morphogenetic proteins induce gremlin, a protein that limits their activity in osteoblasts. Endocrinology 141: 4558–4563CrossRefGoogle Scholar
  131. 131.
    Gazzerro E, Pereira RC, Jorgetti V, Olson S, Economides AN, Canalis E (2005) Skeletal overexpression of gremlin impairs bone formation and causes osteopenia. Endocrinology 146: 655–665CrossRefGoogle Scholar
  132. 132.
    Topol LZ, Bardot B, Zhang Q, Resau J, Huillard E, Marx M, Calothy G, Blair DG (2000) Biosynthesis, post-translation modification, and functional characterization of Drm/Gremlin. J Biol Chem 275: 8785–8793CrossRefGoogle Scholar
  133. 133.
    Topol LZ, Modi WS, Koochekpour S, Blair DG (2000) DRM/GREMLIN (CKTSF1B1) maps to human chromosome 15 and is highly expressed in adult and fetal brain. Cytogenet Cell Genet 89: 79–84CrossRefGoogle Scholar
  134. 134.
    Suzuki M, Shigematsu H, Shivapurkar N, Reddy J, Miyajima K, Takahashi T, Gazdar AF, Frenkel EP (2006) Methylation of apoptosis related genes in the pathogenesis and prognosis of prostate cancer. Cancer Lett 242: 222–230CrossRefGoogle Scholar
  135. 135.
    Chen B, Athanasiou M, Gu Q, Blair DG (2002) Drm/Gremlin transcriptionally activates p21(Cip1) via a novel mechanism and inhibits neoplastic transformation. Biochem Biophys Res Commun 295: 1135–1141CrossRefGoogle Scholar
  136. 136.
    Yanagita M, Oka M, Watabe T, Iguchi H, Niida A, Takahashi S, Akiyama T, Miyazono K, Yanagisawa M, Sakurai T (2004) USAG-1: A bone morphogenetic protein antagonist abundantly expressed in the kidney. Biochem Biophys Res Commun 316: 490–500CrossRefGoogle Scholar
  137. 137.
    Laurikkala J, Kassai Y, Pakkasjarvi L, Thesleff I, Itoh N (2003) Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot. Dev Biol 264: 91–105CrossRefGoogle Scholar
  138. 138.
    Simmons DG, Kennedy TG (2002) Uterine sensitization-associated gene-1: a novel gene induced within the rat endometrium at the time of uterine receptivity/sensitization for the decidual cell reaction. Biol Reprod 67: 1638–1645CrossRefGoogle Scholar
  139. 139.
    Itasaki N, Jones CM, Mercurio S, Rowe A, Domingos PM, Smith JC, Krumlauf R (2003) Wise, a context-dependent activator and inhibitor of Wnt signalling. Development 130: 4295–4305CrossRefGoogle Scholar
  140. 140.
    Sokol SY (1996) Analysis of Dishevelled signalling pathways during Xenopus development. Curr Biol 6: 1456–1467CrossRefGoogle Scholar
  141. 141.
    Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X (2000) LDL-receptor-related proteins in Wnt signal transduction. Nature 407: 530–535CrossRefGoogle Scholar
  142. 142.
    Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo PJ, Fu Y et al (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68: 577–589CrossRefGoogle Scholar
  143. 143.
    Beighton P (1988) Sclerosteosis. J Med Genet 25: 200–203CrossRefGoogle Scholar
  144. 144.
    Beighton P, Davidson J, Durr L, Hamersma H (1977) Sclerosteosis — An autosomal recessive disorder. Clin Genet 11: 1–7CrossRefGoogle Scholar
  145. 145.
    Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P et al (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10: 537–543CrossRefGoogle Scholar
  146. 146.
    Jacobs P (1977) Van Buchem disease. Postgrad Med J 53: 497–506Google Scholar
  147. 147.
    Van Buchem FS, Hadders HN, Ubbens R (1955) An uncommon familial systemic disease of the skeleton: Hyperostosis corticalis generalisata familiaris. Acta Radiol 44: 109–120CrossRefGoogle Scholar
  148. 148.
    Kusu N, Laurikkala J, Imanishi M, Usui H, Konishi M, Miyake A, Thesleff I, Itoh N (2003) Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity. J Biol Chem 278: 24113–24117CrossRefGoogle Scholar
  149. 149.
    Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, Shpektor D, Jonas M, Kovacevich BR, Staehling-Hampton K et al (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22: 6267–6276CrossRefGoogle Scholar
  150. 150.
    Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, Reeve J (2005) Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 19: 1842–1844Google Scholar
  151. 151.
    Sutherland MK, Geoghegan JC, Yu C, Turcott E, Skonier JE, Winkler DG, Latham JA (2004) Sclerostin promotes the apoptosis of human osteoblastic cells: A novel regulation of bone formation. Bone 35: 828–835CrossRefGoogle Scholar
  152. 152.
    van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst G, Karperien M, Quax PH, Vrieling H, Papapoulos SE, ten Dijke P et al (2007) Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. J Bone Miner Res 22: 19–28CrossRefGoogle Scholar
  153. 153.
    van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M, Hamersma H, Papapoulos SE, ten Dijke P, Lowik CW (2004) Sclerostin is an osteocyteexpressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199: 805–814CrossRefGoogle Scholar
  154. 154.
    Ohyama Y, Nifuji A, Maeda Y, Amagasa T, Noda M (2004) Spaciotemporal association and bone morphogenetic protein regulation of sclerostin and osterix expression during embryonic osteogenesis. Endocrinology 145: 4685–4692CrossRefGoogle Scholar
  155. 155.
    Sutherland MK, Geoghegan JC, Yu C, Winkler DG, Latham JA (2004) Unique regulation of SOST, the sclerosteosis gene, by BMPs and steroid hormones in human osteoblasts. Bone 35: 448–454CrossRefGoogle Scholar
  156. 156.
    Winkler DG, Yu C, Geoghegan JC, Ojala EW, Skonier JE, Shpektor D, Sutherland MK, Latham JA (2004) Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex. J Biol Chem 279: 36293–36298CrossRefGoogle Scholar
  157. 157.
    Mason ED, Konrad KD, Webb CD, Marsh JL (1994) Dorsal midline fate in Drosophila embryos requires twisted gastrulation, a gene encoding a secreted protein related to human connective tissue growth factor. Genes Dev 8: 1489–1501CrossRefGoogle Scholar
  158. 158.
    Oelgeschlager M, Larrain J, Geissert D, De Robertis EM (2000) The evolutionarily conserved BMP-binding protein Twisted gastrulation promotes BMP signalling. Nature 405: 757–763CrossRefGoogle Scholar
  159. 159.
    Chang C, Holtzman DA, Chau S, Chickering T, Woolf EA, Holmgren LM, Bodorova J, Gearing DP, Holmes WE, Brivanlou AH (2001) Twisted gastrulation can function as a BMP antagonist. Nature 410: 483–487CrossRefGoogle Scholar
  160. 160.
    Scott IC, Blitz IL, Pappano WN, Maas SA, Cho KW, Greenspan DS (2001) Homologues of Twisted gastrulation are extracellular cofactors in antagonism of BMP signalling. Nature 410: 475–478CrossRefGoogle Scholar
  161. 161.
    Ross JJ, Shimmi O, Vilmos P, Petryk A, Kim H, Gaudenz K, Hermanson S, Ekker SC, O’Connor MB, Marsh JL (2001) Twisted gastrulation is a conserved extracellular BMP antagonist. Nature 410: 479–483CrossRefGoogle Scholar
  162. 162.
    Gazzerro E, Deregowski V, Vaira S, Canalis E (2005) Overexpression of twisted gastrulation inhibits bone morphogenetic protein action and prevents osteoblast cell differentiation in vitro. Endocrinology 146: 3875–3882CrossRefGoogle Scholar
  163. 163.
    Petryk A, Shimmi O, Jia X, Carlson AE, Tervonen L, Jarcho MP, O’Connor MB, Gopalakrishnan R (2005) Twisted gastrulation and chordin inhibit differentiation and mineralization in MC3T3-E1 osteoblast-like cells. Bone 36: 617–626CrossRefGoogle Scholar
  164. 164.
    Aspenberg P, Jeppsson C, Economides AN (2001) The bone morphogenetic proteins antagonist Noggin inhibits membranous ossification. J Bone Miner Res 16: 497–500CrossRefGoogle Scholar
  165. 165.
    Zimmerman LB, De Jesus-Escobar JM, Harland RM (1996) The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 86: 599–606CrossRefGoogle Scholar
  166. 166.
    Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN, Kwiatkowski W, Affolter M, Vale WW, Belmonte JC, Choe S (2002) Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420: 636–642CrossRefGoogle Scholar
  167. 167.
    Anderson RM, Lawrence AR, Stottmann RW, Bachiller D, Klingensmith J (2002) Chordin and noggin promote organizing centers of forebrain development in the mouse. Development 129: 4975–4987Google Scholar
  168. 168.
    Smith WC, Harland RM (1992) Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos. Cell 70: 829–840CrossRefGoogle Scholar
  169. 169.
    Dionne MS, Brunet LJ, Eimon PM, Harland RM (2002) Noggin is required for correct guidance of dorsal root ganglion axons. Dev Biol 251: 283–293CrossRefGoogle Scholar
  170. 170.
    Wan DC, Pomerantz JH, Brunet LJ, Kim JB, Chou YF, Wu BM, Harland R, Blau HM, Longaker MT (2007) Noggin suppression enhances in vitro osteogenesis and accelerates in vivo bone formation. J Biol Chem 282: 26450–26459CrossRefGoogle Scholar
  171. 171.
    Brunet LJ, McMahon JA, McMahon AP, Harland RM (1998) Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 280: 1455–1457CrossRefGoogle Scholar
  172. 172.
    Gazzerro E, Gangji V, Canalis E (1998) Bone morphogenetic proteins induce the expression of noggin, which limits their activity in cultured rat osteoblasts. J Clin Invest 102: 2106–2114CrossRefGoogle Scholar
  173. 173.
    Abe E, Yamamoto M, Taguchi Y, Lecka-Czernik B, O’Brien CA, Economides AN, Stahl N, Jilka RL, Manolagas SC (2000) Essential requirement of BMPs-2/4 for both osteoblast and osteoclast formation in murine bone marrow cultures from adult mice: Antagonism by noggin. J Bone Miner Res 15: 663–673CrossRefGoogle Scholar
  174. 174.
    Pathi S, Rutenberg JB, Johnson RL, Vortkamp A (1999) Interaction of Ihh and BMP/ Noggin signaling during cartilage differentiation. Dev Biol 209: 239–253CrossRefGoogle Scholar
  175. 175.
    Gong Y, Krakow D, Marcelino J, Wilkin D, Chitayat D, Babul-Hirji R, Hudgins L, Cremers CW, Cremers FP, Brunner HG et al (1999) Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis. Nat Genet 21: 302–304CrossRefGoogle Scholar
  176. 176.
    Marcelino J, Sciortino CM, Romero MF, Ulatowski LM, Ballock RT, Economides AN, Eimon PM, Harland RM, Warman ML (2001) Human disease-causing NOG missense mutations: Effects on noggin secretion, dimer formation, and bone morphogenetic protein binding. Proc Natl Acad Sci USA 98: 11353–11358CrossRefGoogle Scholar
  177. 177.
    Piccolo S, Sasai Y, Lu B, De Robertis EM (1996) Dorsoventral patterning in Xenopus: Inhibition of ventral signals by direct binding of chordin to BMP-4. Cell 86: 589–598CrossRefGoogle Scholar
  178. 178.
    Sasai Y, Lu B, Piccolo S, De Robertis EM (1996) Endoderm induction by the organizersecreted factors chordin and noggin in Xenopus animal caps. EMBO J 15: 4547–4555Google Scholar
  179. 179.
    Bachiller D, Klingensmith J, Kemp C, Belo JA, Anderson RM, May SR, McMahon JA, McMahon AP, Harland RM, Rossant J et al (2000) The organizer factors Chordin and Noggin are required for mouse forebrain development. Nature 403: 658–661CrossRefGoogle Scholar
  180. 180.
    Larrain J, Bachiller D, Lu B, Agius E, Piccolo S, De Robertis EM (2000) BMP-binding modules in chordin: A model for signalling regulation in the extracellular space. Development 127: 821–830Google Scholar
  181. 181.
    Scott IC, Blitz IL, Pappano WN, Imamura Y, Clark TG, Steiglitz BM, Thomas CL, Maas SA, Takahara K, Cho KW et al (1999) Mammalian BMP-1/Tolloid-related metalloproteinases, including novel family member mammalian Tolloid-like 2, have differential enzymatic activities and distributions of expression relevant to patterning and skeletogenesis. Dev Biol 213: 283–300CrossRefGoogle Scholar
  182. 182.
    Zhang D, Ferguson CM, O’Keefe RJ, Puzas JE, Rosier RN, Reynolds PR (2002) A role for the BMP antagonist chordin in endochondral ossification. J Bone Miner Res 17: 293–300CrossRefGoogle Scholar
  183. 183.
    Reynolds SD, Zhang D, Puzas JE, O’Keefe RJ, Rosier RN, Reynolds PR (2000) Cloning of the chick BMP1/Tolloid cDNA and expression in skeletal tissues. Gene 248: 233–243CrossRefGoogle Scholar
  184. 184.
    Moreno M, Munoz R, Aroca F, Labarca M, Brandan E, Larrain J (2005) Biglycan is a new extracellular component of the Chordin-BMP-4 signaling pathway. EMBO J 24: 1397–1405CrossRefGoogle Scholar
  185. 185.
    Koike N, Kassai Y, Kouta Y, Miwa H, Konishi M, Itoh N (2007) Brorin, a novel secreted bone morphogenetic protein antagonist, promotes neurogenesis in mouse neural precursor cells. J Biol Chem 282: 15843–15850CrossRefGoogle Scholar
  186. 186.
    Garcia Abreu J, Coffinier C, Larrain J, Oelgeschlager M, De Robertis EM (2002) Chordin-like CR domains and the regulation of evolutionarily conserved extracellular signaling systems. Gene 287: 39–47Google Scholar
  187. 187.
    French DM, Kaul RJ, D’Souza AL, Crowley CW, Bao M, Frantz GD, Filvaroff EH, Desnoyers L (2004) WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repair. Am J Pathol 165: 855–867Google Scholar
  188. 188.
    Onichtchouk D, Chen YG, Dosch R, Gawantka V, Delius H, Massague J, Niehrs C (1999) Silencing of TGF-beta signalling by the pseudoreceptor BAMBI. Nature 401: 480–485CrossRefGoogle Scholar
  189. 189.
    Samad TA, Rebbapragada A, Bell E, Zhang Y, Sidis Y, Jeong SJ, Campagna JA, Perusini S, Fabrizio DA, Schneyer AL et al (2005) DRAGON, a bone morphogenetic protein coreceptor. J Biol Chem 280: 14122–14129CrossRefGoogle Scholar
  190. 190.
    Samad TA, Srinivasan A, Karchewski LA, Jeong SJ, Campagna JA, Ji RR, Fabrizio DA, Zhang Y, Lin HY, Bell E et al (2004) DRAGON: A member of the repulsive guidance molecule-related family of neuronal-and muscle-expressed membrane proteins is regulated by DRG11 and has neuronal adhesive properties. J Neurosci 24: 2027–2036CrossRefGoogle Scholar
  191. 191.
    Babitt JL, Zhang Y, Samad TA, Xia Y, Tang J, Campagna JA, Schneyer AL, Woolf CJ, Lin HY (2005) Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor. J Biol Chem 280: 29820–29827CrossRefGoogle Scholar
  192. 192.
    Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ et al (2006) Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 38: 531–539CrossRefGoogle Scholar
  193. 193.
    Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY (2007) Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest 117: 1933–1939CrossRefGoogle Scholar
  194. 194.
    Halbrooks PJ, Ding R, Wozney JM, Bain G (2007) Role of RGM coreceptors in bone morphogenetic protein signaling. J Mol Signal 2: 4CrossRefGoogle Scholar
  195. 195.
    Afzal AR, Rajab A, Fenske CD, Oldridge M, Elanko N, Ternes-Pereira E, Tuysuz B, Murday VA, Patton MA, Wilkie AO et al (2000) Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2. Nat Genet 25: 419–422CrossRefGoogle Scholar
  196. 196.
    Schwabe GC, Tinschert S, Buschow C, Meinecke P, Wolff G, Gillessen-Kaesbach G, Oldridge M, Wilkie AO, Komec R, Mundlos S (2000) Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B. Am J Hum Genet 67: 822–831CrossRefGoogle Scholar
  197. 197.
    Sammar M, Stricker S, Schwabe GC, Sieber C, Hartung A, Hanke M, Oishi I, Pohl J, Minami Y, Sebald W et al (2004) Modulation of GDF-5/BRI-b signalling through interaction with the tyrosine kinase receptor Ror2. Genes Cells 9: 1227–1238CrossRefGoogle Scholar
  198. 198.
    Hassel S, Yakymovych M, Hellman U, Ronnstrand L, Knaus P, Souchelnytskyi S (2006) Interaction and functional cooperation between the serine/threonine kinase bone morphogenetic protein type II receptor with the tyrosine kinase stem cell factor receptor. J Cell Physiol 206: 457–467CrossRefGoogle Scholar
  199. 199.
    Drissi MH, Li X, Sheu TJ, Zuscik MJ, Schwarz EM, Puzas JE, Rosier RN, O’Keefe RJ (2003) Runx2/Cbfa1 stimulation by retinoic acid is potentiated by BMP-2 signaling through interaction with Smad1 on the collagen X promoter in chondrocytes. J Cell Biochem 90: 1287–1298CrossRefGoogle Scholar
  200. 200.
    Leboy P, Grasso-Knight G, D’Angelo M, Volk SW, Lian JV, Drissi H, Stein GS, Adams SL (2001) Smad-Runx interactions during chondrocyte maturation. J Bone Joint Surg Am 83-A Suppl 1: S15–22Google Scholar
  201. 201.
    Nishio Y, Dong Y, Paris M, O’Keefe RJ, Schwarz EM, Drissi H (2006) Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene. Gene 372: 62–70CrossRefGoogle Scholar
  202. 202.
    Ito Y, Miyazono K (2003) RUNX transcription factors as key targets of TGF-beta superfamily signaling. Curr Opin Genet Dev 13: 43–47CrossRefGoogle Scholar
  203. 203.
    Lee KS, Kim HJ, Li QL, Chi XZ, Ueta C, Komori T, Wozney JM, Kim EG, Choi JY, Ryoo HM et al (2000) Runx2 is a common target of transforming growth factor beta1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12. Mol Cell Biol 20: 8783–8792CrossRefGoogle Scholar
  204. 204.
    Lee MH, Kim YJ, Kim HJ, Park HD, Kang AR, Kyung HM, Sung JH, Wozney JM, Kim HJ, Ryoo HM (2003) BMP-2-induced Runx2 expression is mediated by Dlx5, and TGF-beta 1 opposes the BMP-2-induced osteoblast differentiation by suppression of Dlx5 expression. J Biol Chem 278: 34387–34394CrossRefGoogle Scholar
  205. 205.
    Akhurst RJ, Derynck R (2001) TGF-beta signaling in cancer — A double-edged sword. Trends Cell Biol 11: S44–51Google Scholar
  206. 206.
    Monzen K, Hiroi Y, Kudoh S, Akazawa H, Oka T, Takimoto E, Hayashi D, Hosoda T, Kawabata M, Miyazono K et al (2001) Smads, TAK1, and their common target ATF-2 play a critical role in cardiomyocyte differentiation. J Cell Biol 153: 687–698CrossRefGoogle Scholar
  207. 207.
    Bond HM, Mesuraca M, Carbone E, Bonelli P, Agosti V, Amodio N, De Rosa G, Di Nicola M, Gianni AM, Moore MA et al (2004) Early hematopoietic zinc finger protein (EHZF), the human homolog to mouse Evi3, is highly expressed in primitive human hematopoietic cells. Blood 103: 2062–2070CrossRefGoogle Scholar
  208. 208.
    Hata A, Seoane J, Lagna G, Montalvo E, Hemmati-Brivanlou A, Massague J (2000) OAZ uses distinct DNA-and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways. Cell 100: 229–240CrossRefGoogle Scholar
  209. 209.
    de Caestecker MP, Yahata T, Wang D, Parks WT, Huang S, Hill CS, Shioda T, Roberts AB, Lechleider RJ (2000) The Smad4 activation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain. J Biol Chem 275: 2115–2122CrossRefGoogle Scholar
  210. 210.
    Pearson KL, Hunter T, Janknecht R (1999) Activation of Smad1-mediated transcription by p300/CBP. Biochim Biophys Acta 1489: 354–364Google Scholar
  211. 211.
    Kahata K, Hayashi M, Asaka M, Hellman U, Kitagawa H, Yanagisawa J, Kato S, Imamura T, Miyazono K (2004) Regulation of transforming growth factor-beta and bone morphogenetic protein signalling by transcriptional coactivator GCN5. Genes Cells 9: 143–151CrossRefGoogle Scholar
  212. 212.
    Bai RY, Koester C, Ouyang T, Hahn SA, Hammerschmidt M, Peschel C, Duyster J (2002) SMIF, a Smad4-interacting protein that functions as a co-activator in TGFbeta signalling. Nat Cell Biol 4: 181–190CrossRefGoogle Scholar
  213. 213.
    Henningfeld KA, Friedle H, Rastegar S, Knochel W (2002) Autoregulation of Xvent-2B; direct interaction and functional cooperation of Xvent-2 and Smad1. J Biol Chem 277: 2097–2103CrossRefGoogle Scholar
  214. 214.
    Postigo AA (2003) Opposing functions of ZEB proteins in the regulation of the TGFbeta/ BMP signaling pathway. EMBO J 22: 2443–2452CrossRefGoogle Scholar
  215. 215.
    Postigo AA, Depp JL, Taylor JJ, Kroll KL (2003) Regulation of Smad signaling through a differential recruitment of coactivators and corepressors by ZEB proteins. EMBO J 22: 2453–2462CrossRefGoogle Scholar
  216. 216.
    van Grunsven LA, Schellens A, Huylebroeck D, Verschueren K (2001) SIP1 (Smad interacting protein 1) and deltaEF1 (delta-crystallin enhancer binding factor) are structurally similar transcriptional repressors. J Bone Joint Surg Am 83-A Suppl 1: S40–47Google Scholar
  217. 217.
    Sowa H, Kaji H, Hendy GN, Canaff L, Komori T, Sugimoto T, Chihara K (2004) Menin is required for bone morphogenetic protein 2-and transforming growth factor betaregulated osteoblastic differentiation through interaction with Smads and Runx2. J Biol Chem 279: 40267–40275CrossRefGoogle Scholar
  218. 218.
    Bai S, Shi X, Yang X, Cao X (2000) Smad6 as a transcriptional corepressor. J Biol Chem 275: 8267–8270CrossRefGoogle Scholar
  219. 219.
    Shi X, Yang X, Chen D, Chang Z, Cao X (1999) Smad1 interacts with homeobox DNA-binding proteins in bone morphogenetic protein signaling. J Biol Chem 274: 13711–13717CrossRefGoogle Scholar
  220. 220.
    Jiao K, Zhou Y, Hogan BL (2002) Identification of mZnf8, a mouse Kruppel-like transcriptional repressor, as a novel nuclear interaction partner of Smad1. Mol Cell Biol 22: 7633–7644CrossRefGoogle Scholar
  221. 221.
    Provot S, Kempf H, Murtaugh LC, Chung UI, Kim DW, Chyung J, Kronenberg HM, Lassar AB (2006) Nkx3.2/Bapx1 acts as a negative regulator of chondrocyte maturation. Development133: 651–662CrossRefGoogle Scholar
  222. 222.
    Kim DW, Kempf H, Chen RE, Lassar AB (2003) Characterization of Nkx3.2 DNA binding specificity and its requirement for somitic chondrogenesis. J Biol Chem 278: 27532–27539CrossRefGoogle Scholar
  223. 223.
    Kurisaki K, Kurisaki A, Valcourt U, Terentiev AA, Pardali K, Ten Dijke P, Heldin CH, Ericsson J, Moustakas A (2003) Nuclear factor YY1 inhibits transforming growth factor beta-and bone morphogenetic protein-induced cell differentiation. Mol Cell Biol23: 4494–4510CrossRefGoogle Scholar
  224. 224.
    Lee KH, Evans S, Ruan TY, Lassar AB (2004) SMAD-mediated modulation of YY1 activity regulates the BMP response and cardiac-specific expression of a GATA4/5/6-dependent chick Nkx2.5 enhancer. Development 131: 4709–4723CrossRefGoogle Scholar
  225. 225.
    Wu JW, Krawitz AR, Chai J, Li W, Zhang F, Luo K, Shi Y (2002) Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: Insights on Ski-mediated repression of TGF-beta signaling. Cell 111: 357–367CrossRefGoogle Scholar
  226. 226.
    Wang W, Mariani FV, Harland RM, Luo K (2000) Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells. Proc Natl Acad Sci USA 97: 14394–14399CrossRefGoogle Scholar
  227. 227.
    Luo K (2003) Negative regulation of BMP signaling by the ski oncoprotein. J Bone Joint Surg Am 85-ASuppl 3: 39–43Google Scholar
  228. 228.
    Luo K (2004) Ski and SnoN: negative regulators of TGF-beta signaling. Curr Opin Genet Dev 14: 65–70CrossRefGoogle Scholar
  229. 229.
    Wu K, Yang Y, Wang C, Davoli MA, D’Amico M, Li A, Cveklova K, Kozmik Z, Lisanti MP, Russell RG et al (2003) DACH1 inhibits transforming growth factor-beta signaling through binding Smad4. J Biol Chem 278: 51673–51684CrossRefGoogle Scholar
  230. 230.
    Yoshida Y, Tanaka S, Umemori H, Minowa O, Usui M, Ikematsu N, Hosoda E, Imamura T, Kuno J, Yamashita T et al (2000) Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 103: 1085–1097CrossRefGoogle Scholar
  231. 231.
    Yoshida Y, von Bubnoff A, Ikematsu N, Blitz IL, Tsuzuku JK, Yoshida EH, Umemori H, Miyazono K, Yamamoto T, Cho KW (2003) Tob proteins enhance inhibitory Smadreceptor interactions to repress BMP signaling. Mech Dev 120: 629–637CrossRefGoogle Scholar
  232. 232.
    Tylzanowski P, Verschueren K, Huylebroeck D, Luyten FP (2001) Smad-interacting protein 1 is a repressor of liver/bone/kidney alkaline phosphatase transcription in bone morphogenetic protein-induced osteogenic differentiation of C2C12 cells. J Biol Chem 276: 40001–40007CrossRefGoogle Scholar
  233. 233.
    Verschueren K, Remacle JE, Collart C, Kraft H, Baker BS, Tylzanowski P, Nelles L, Wuytens G, Su MT, Bodmer R et al (1999) SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5′-CACCT sequences in candidate target genes. J Biol Chem 274: 20489–20498CrossRefGoogle Scholar
  234. 234.
    Lin X, Liang YY, Sun B, Liang M, Shi Y, Brunicardi FC, Shi Y, Feng XH (2003) Smad6 recruits transcription corepressor CtBP to repress bone morphogenetic protein-induced transcription. Mol Cell Biol 23: 9081–9093CrossRefGoogle Scholar
  235. 235.
    Kim RH, Wang D, Tsang M, Martin J, Huff C, de Caestecker MP, Parks WT, Meng X, Lechleider RJ, Wang T et al (2000) A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction. Genes Dev 14: 1605–1616Google Scholar
  236. 236.
    Lin Y, Martin J, Gruendler C, Farley J, Meng X, Li BY, Lechleider R, Huff C, Kim RH, Grasser WA et al (2002) A novel link between the proteasome pathway and the signal transduction pathway of the bone morphogenetic proteins (BMPs). BMC Cell Biol 3: 15CrossRefGoogle Scholar
  237. 237.
    Ogasawara T, Kawaguchi H, Jinno S, Hoshi K, Itaka K, Takato T, Nakamura K, Okayama H (2004) Bone morphogenetic protein 2-induced osteoblast differentiation requires Smad-mediated down-regulation of Cdk6. Mol Cell Biol 24: 6560–6568CrossRefGoogle Scholar
  238. 238.
    Raju GP, Dimova N, Klein PS, Huang HC (2003) SANE, a novel LEM domain protein, regulates bone morphogenetic protein signaling through interaction with Smad1. J Biol Chem 278: 428–437CrossRefGoogle Scholar
  239. 239.
    Shen ZJ, Nakamoto T, Tsuji K, Nifuji A, Miyazono K, Komori T, Hirai H, Noda M (2002) Negative regulation of bone morphogenetic protein/Smad signaling by Cas-interacting zinc finger protein in osteoblasts. J Biol Chem 277: 29840–29846CrossRefGoogle Scholar
  240. 240.
    Kurozumi K, Nishita M, Yamaguchi K, Fujita T, Ueno N, Shibuya H (1998) BRAM1, a BMP receptor-associated molecule involved in BMP signalling. Genes Cells 3: 257–264CrossRefGoogle Scholar
  241. 241.
    Satow R, Kurisaki A, Chan TC, Hamazaki TS, Asashima M (2006) Dullard promotes degradation and dephosphorylation of BMP receptors and is required for neural induction. Dev Cell 11: 763–774CrossRefGoogle Scholar
  242. 242.
    Chan MC, Nguyen PH, Davis BN, Ohoka N, Hayashi H, Du K, Lagna G, Hata A (2007) A novel regulatory mechanism of the bone morphogenetic protein (BMP) signaling pathway Involving the carboxyl-terminal tail domain of BMP type II receptor. Mol Cell Biol 27: 5776–5789CrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2008

Authors and Affiliations

  • Christina Sieber
    • 1
  • Gerburg K. Schwaerzer
    • 1
  • Petra Knaus
    • 1
  1. 1.Institute for Chemistry/BiochemistryFreie Universität BerlinBerlinGermany

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