Skip to main content
SpringerLink
Log in

Signaling cross-talk by bone morphogenetic proteins

  • Chapter
Book cover Bone Morphogenetic Proteins: From Local to Systemic Therapeutics

Part of the book series: Progress in Inflammation Research ((PIR))

  • 981 Accesses

Abstract

Bone morphogenetic proteins (BMPs) have diverse effect on different cell types and, for many, BMPs play essential role in their survival and differentiation. BMPs are conserved across the animal kingdom and participate in the development of a wide variety of organisms including vertebrates, arthropods and nematodes. In the growing family of BMPs, more than 30 members have been described so far. In vertebrates, BMPs regulate development of many organs, including heart, kidney and bone, by regulating proliferation, differentiation and apoptotic pathways [1–3]. The wide spectrum of biological responses elicited by BMPs in different cellular set ups are dictated by tightly controlled signaling cross-talk between BMPinduced signaling pathways and interaction of divergent intracellular cofactors. In this review, we describe the signal transduction pathways induced by BMPs and discuss the possible cross-talk between them. We focus mainly on BMP signaling in bone with a brief discussion of other cell types that are regulated by BMPs. Figure 1 summarizes the pathways for BMP-induced signal transduction pathways discussed in this review.

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 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
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

  1. Hogan BL (1996) Bone morphogenetic proteins in development. Curr Opin Genet Dev 6: 432–438

    Article  CAS  Google Scholar 

  2. Hogan BL (1996) Bone morphogenetic proteins: Multifunctional regulators of vertebrate development. Genes Dev 10: 1580–1594

    Article  CAS  Google Scholar 

  3. Gambaro K, Aberdam E, Virolle T, Aberdam D, Rouleau M (2006) BMP-4 induces a Smad-dependent apoptotic cell death of mouse embryonic stem cell-derived neural precursors. Cell Death Differ 13: 1075–1087

    Article  CAS  Google Scholar 

  4. Kawabata M, Imamura T, Miyazono K (1998) Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev 9: 49–61

    Article  CAS  Google Scholar 

  5. Miyazono K, Maeda S, Imamura T (2005) BMP receptor signaling: Transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev 16: 251–263

    Article  CAS  Google Scholar 

  6. ten Dijke P, Fu J, Schaap P, Roelen BA (2003) Signal transduction of bone morphogenetic proteins in osteoblast differentiation. J Bone Joint Surg Am 85-ASuppl 3: 34–38

    Google Scholar 

  7. Koenig BB, Cook JS, Wolsing DH, Ting J, Tiesman JP, Correa PE, Olson CA, Pecquet AL, Ventura F, Grant RA et al (1994) Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells. Mol Cell Biol 14: 5961–5974

    CAS  Google Scholar 

  8. 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: 22522–22526

    Article  CAS  Google Scholar 

  9. 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: 7632–7636

    Article  CAS  Google Scholar 

  10. 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: 16985–16988

    Google Scholar 

  11. 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: 3479–3486

    CAS  Google Scholar 

  12. 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: 5330–5338

    Article  CAS  Google Scholar 

  13. Fujii M, Takeda K, Imamura T, Aoki H, Sampath TK, Enomoto S, Kawabata M, Kato M, Ichijo H, Miyazono K (1999) Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation. Mol Biol Cell 10: 3801–3813

    CAS  Google Scholar 

  14. Miyazono K (1999) Signal transduction by bone morphogenetic protein receptors: Functional roles of Smad proteins. Bone 25: 91–93

    Article  CAS  Google Scholar 

  15. Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA Jr, Wrana JL et al (1997) The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell 89: 1165–1173

    Article  CAS  Google Scholar 

  16. Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M, Miyazono K (1997) Smad6 inhibits signalling by the TGF-beta superfamily. Nature 389: 622–626

    Article  CAS  Google Scholar 

  17. Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH et al (1997) Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 389: 631–635

    Article  CAS  Google Scholar 

  18. Topper JN, Cai J, Qiu Y, Anderson KR, Xu YY, Deeds JD, Feeley R, Gimeno CJ, Woolf EA, Tayber O et al (1997) Vascular MADs: Two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Proc Natl Acad Sci USA 94: 9314–9319

    Article  CAS  Google Scholar 

  19. Topper JN, Wasserman SM, Anderson KR, Cai J, Falb D, Gimbrone MA Jr (1997) Expression of the bumetanide-sensitive Na-K-Cl cotransporter BSC2 is differentially regulated by fluid mechanical and inflammatory cytokine stimuli in vascular endothelium. J Clin Invest 99: 2941–2949

    Article  CAS  Google Scholar 

  20. Ku M, Howard S, Ni W, Lagna G, Hata A (2006) OAZ regulates bone morphogenetic protein signaling through Smad6 activation. J Biol Chem 281: 5277–5287

    Article  CAS  Google Scholar 

  21. 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: 229–240

    Article  CAS  Google Scholar 

  22. Casellas R, Brivanlou AH (1998) Xenopus Smad7 inhibits both the activin and BMP pathways and acts as a neural inducer. Dev Biol 198: 1–12

    Article  CAS  Google Scholar 

  23. Nakayama T, Gardner H, Berg LK, Christian JL (1998) Smad6 functions as an intracellular antagonist of some TGF-beta family members during Xenopus embryogenesis. Genes Cells 3: 387–394

    Article  CAS  Google Scholar 

  24. Tsuneizumi K, Nakayama T, Kamoshida Y, Kornberg TB, Christian JL, Tabata T (1997) Daughters against dpp modulates dpp organizing activity in Drosophila wing development. Nature 389: 627–631

    Article  CAS  Google Scholar 

  25. 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  CAS  Google Scholar 

  26. 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: 687–693

    Article  CAS  Google Scholar 

  27. Kretzschmar M, Doody J, Massague J (1997) Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature 389: 618–622

    Article  CAS  Google Scholar 

  28. Massague J (2003) Integration of Smad and MAPK pathways: A link and a linker revisited. Genes Dev 17: 2993–2997

    Article  CAS  Google Scholar 

  29. Pera EM, Ikeda A, Eivers E, De Robertis EM (2003) Integration of IGF, FGF, and anti-BMP signals via Smad1 phosphorylation in neural induction. Genes Dev 17: 3023–3028

    Article  CAS  Google Scholar 

  30. Yue J, Frey RS, Mulder KM (1999) Cross-talk between the Smad1 and Ras/MEK signaling pathways for TGFbeta. Oncogene 18: 2033–2037

    Article  CAS  Google Scholar 

  31. Kretzschmar M, Doody J, Timokhina I, Massague J (1999) A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. Genes Dev 13: 804–816

    Article  CAS  Google Scholar 

  32. De Robertis EM, Larrain J, Oelgeschlager M, Wessely O (2000) The establishment of Spemann’s organizer and patterning of the vertebrate embryo. Nat Rev Genet 1: 171–181

    Article  CAS  Google Scholar 

  33. Kretzschmar M, Liu F, Hata A, Doody J, Massague J (1997) The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase. Genes Dev 11: 984–995

    Article  CAS  Google Scholar 

  34. Aubin J, Davy A, Soriano P (2004) In vivo convergence of BMP and MAPK signaling pathways: Impact of differential Smad1 phosphorylation on development and homeostasis. Genes Dev 18: 1482–1494

    Article  CAS  Google Scholar 

  35. Sapkota G, Alarcon C, Spagnoli FM, Brivanlou AH, Massague J (2007) Balancing BMP signaling through integrated inputs into the Smad1 linker. Mol Cell 25: 441–454

    Article  CAS  Google Scholar 

  36. 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: 15514–15522

    Article  CAS  Google Scholar 

  37. 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: 1023–1035

    CAS  Google Scholar 

  38. Knaus P, Sebald W (2001) Cooperativity of binding epitopes and receptor chains in the BMP/TGFbeta superfamily. Biol Chem 382: 1189–1195

    Article  CAS  Google Scholar 

  39. 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: 179–187

    Article  CAS  Google Scholar 

  40. 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: 8141–8144

    Article  CAS  Google Scholar 

  41. Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T (2000) BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem 275: 17647–17652

    Article  CAS  Google Scholar 

  42. Cadigan KM, Nusse R (1997) Wnt signaling: A common theme in animal development. Genes Dev 11: 3286–3305

    Article  CAS  Google Scholar 

  43. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D et al (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107: 513–523

    Article  CAS  Google Scholar 

  44. Ai M, Holmen SL, Van Hul W, Williams BO, Warman ML (2005) Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Mol Cell Biol 25: 4946–4955

    Article  CAS  Google Scholar 

  45. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346: 1513–1521

    Article  CAS  Google Scholar 

  46. Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Benichou O, Scopelliti D, Key L, Renton T, Bartels C, Gong Y et al (2003) Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet 72: 763–771

    Article  Google Scholar 

  47. Akiyama T (2000) Wnt/beta-catenin signaling. Cytokine Growth Factor Rev 11: 273–282

    Article  CAS  Google Scholar 

  48. Brown JD, Moon RT (1998) Wnt signaling: Why is everything so negative? Curr Opin Cell Biol 10: 182–187

    Article  CAS  Google Scholar 

  49. Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S, Kikuchi A (1998) Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and betacatenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J 17: 1371–1384

    Article  CAS  Google Scholar 

  50. Lee JS, Ishimoto A, Yanagawa S (1999) Characterization of mouse dishevelled (Dvl) proteins in Wnt/Wingless signaling pathway. J Biol Chem 274: 21464–21470

    Article  CAS  Google Scholar 

  51. Huelsken J, Behrens J (2002) The Wnt signalling pathway. J Cell Sci 115: 3977–3978

    Article  CAS  Google Scholar 

  52. Huelsken J, Birchmeier W (2001) New aspects of Wnt signaling pathways in higher vertebrates. Curr Opin Genet Dev 11: 547–553

    Article  CAS  Google Scholar 

  53. Ishitani T, Ninomiya-Tsuji J, Nagai S, Nishita M, Meneghini M, Barker N, Waterman M, Bowerman B, Clevers H, Shibuya H et al (1999) The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature 399: 798–802

    Article  CAS  Google Scholar 

  54. Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J, Waterman M, Shibuya H, Moon RT, Ninomiya-Tsuji J, Matsumoto K (2003) The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/ beta-catenin signaling. Mol Cell Biol 23: 131–139

    Article  CAS  Google Scholar 

  55. Nakashima A, Katagiri T, Tamura M (2005) Cross-talk between Wnt and bone morphogenetic protein 2 (BMP-2) signaling in differentiation pathway of C2C12 myoblasts. J Biol Chem 280: 37660–37668

    Article  CAS  Google Scholar 

  56. Yun MS, Kim SE, Jeon SH, Lee JS, Choi KY (2005) Both ERK and Wnt/beta-catenin pathways are involved in Wnt3a-induced proliferation. J Cell Sci 118: 313–322

    Article  CAS  Google Scholar 

  57. Ma L, Wang HY (2007) Mitogen-activated protein kinase p38 regulates the Wnt/cyclic GMP/Ca2+ non-canonical pathway. J Biol Chem 282: 28980–28990

    Article  CAS  Google Scholar 

  58. Baker JC, Beddington RS, Harland RM (1999) Wnt signaling in Xenopus embryos inhibits bmp4 expression and activates neural development. Genes Dev 13: 3149–3159

    Article  CAS  Google Scholar 

  59. Hoppler S, Moon RT (1998) BMP-2/-4 and Wnt-8 cooperatively pattern the Xenopus mesoderm. Mech Dev 71: 119–129

    Article  CAS  Google Scholar 

  60. Marom K, Fainsod A, Steinbeisser H (1999) Patterning of the mesoderm involves several threshold responses to BMP-4 and Xwnt-8. Mech Dev 87: 33–44

    Article  CAS  Google Scholar 

  61. Zimmerman CM, Kariapper MS, Mathews LS (1998) Smad proteins physically interact with calmodulin. J Biol Chem 273: 677–680

    Article  CAS  Google Scholar 

  62. Creton R, Kreiling JA, Jaffe LF (2000) Presence and roles of calcium gradients along the dorsal-ventral axis in Drosophila embryos. Dev Biol 217: 375–385

    Article  CAS  Google Scholar 

  63. Kuhl M, Sheldahl LC, Malbon CC, Moon RT (2000) Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus. J Biol Chem 275: 12701–12711

    Article  CAS  Google Scholar 

  64. Kume S, Muto A, Inoue T, Suga K, Okano H, Mikoshiba K (1997) Role of inositol 1,4,5-trisphosphate receptor in ventral signaling in Xenopus embryos. Science 278: 1940–1943

    Article  CAS  Google Scholar 

  65. Hay E, Lemonnier J, Fromigue O, Marie PJ (2001) Bone morphogenetic protein-2 promotes osteoblast apoptosis through a Smad-independent, protein kinase C-dependent signaling pathway. J Biol Chem 276: 29028–29036

    Article  CAS  Google Scholar 

  66. Gschwendt M, Johannes FJ, Kittstein W, Marks F (1997) Regulation of protein kinase Cmu by basic peptides and heparin. Putative role of an acidic domain in the activation of the kinase. J Biol Chem 272: 20742–20746

    Article  CAS  Google Scholar 

  67. Valverde AM, Sinnett-Smith J, Van Lint J, Rozengurt E (1994) Molecular cloning and characterization of protein kinase D: A target for diacylglycerol and phorbol esters with a distinctive catalytic domain. Proc Natl Acad Sci USA 91: 8572–8576

    Article  CAS  Google Scholar 

  68. Lemonnier J, Ghayor C, Guicheux J, Caverzasio J (2004) Protein kinase C-independent activation of protein kinase D is involved in BMP-2-induced activation of stress mitogen-activated protein kinases JNK and p38 and osteoblastic cell differentiation. J Biol Chem 279: 259–264

    Article  CAS  Google Scholar 

  69. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296: 1655–1657

    Article  CAS  Google Scholar 

  70. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7: 261–269

    Article  CAS  Google Scholar 

  71. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307: 1098–1101

    Article  CAS  Google Scholar 

  72. Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P et al (1998) Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 279: 710–714

    Article  CAS  Google Scholar 

  73. Brazil DP, Park J, Hemmings BA (2002) PKB binding proteins. Getting in on the Akt. Cell 111: 293–303

    Article  CAS  Google Scholar 

  74. Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: A play in three Akts. Genes Dev 13: 2905–2927

    Article  CAS  Google Scholar 

  75. Holland EC, Sonenberg N, Pandolfi PP, Thomas G (2004) Signaling control of mRNA translation in cancer pathogenesis. Oncogene 23: 3138–3144

    Article  CAS  Google Scholar 

  76. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (2005) Rheb binds and regulates the mTOR inase. Curr Biol 15: 702–713

    Article  CAS  Google Scholar 

  77. Long X, Ortiz-Vega S, Lin Y, Avruch J (2005) Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J Biol Chem 280: 23433–23436

    Article  CAS  Google Scholar 

  78. Inoki K, Corradetti MN, Guan KL (2005) Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37: 19–24

    Article  CAS  Google Scholar 

  79. Bellacosa A, Testa JR, Moore R, Larue L (2004) A portrait of AKT kinases: Human cancer and animal models depict a family with strong individualities. Cancer Biol Ther 3: 268–275

    CAS  Google Scholar 

  80. Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, Coskran T, Black SC, Brees DJ, Wicks JR et al (2003) Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest 112: 197–208

    CAS  Google Scholar 

  81. Stiles B, Gilman V, Khanzenzon N, Lesche R, Li A, Qiao R, Liu X, Wu H (2002) Essential role of AKT-1/protein kinase B alpha in PTEN-controlled tumorigenesis. Mol Cell Biol 22: 3842–3851

    Article  CAS  Google Scholar 

  82. Tschopp O, Yang ZZ, Brodbeck D, Dummler BA, Hemmings-Mieszczak M, Watanabe T, Michaelis T, Frahm J, Hemmings BA (2005) Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development 132: 2943–2954

    Article  CAS  Google Scholar 

  83. Kawamura N, Kugimiya F, Oshima Y, Ohba S, Ikeda T, Saito T, Shinoda Y, Kawasaki Y, Ogata N, Hoshi K et al (2007) Akt1 in osteoblasts and osteoclasts controls bone remodeling. PLoS ONE 2: e1058

    Article  CAS  Google Scholar 

  84. Peng XD, Xu PZ, Chen ML, Hahn-Windgassen A, Skeen J, Jacobs J, Sundararajan D, Chen WS, Crawford SE, Coleman KG et al (2003) Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev 17: 1352–1365

    Article  CAS  Google Scholar 

  85. 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: 33361–33368

    Article  CAS  Google Scholar 

  86. Ghosh-Choudhury N, Abboud SL, Mahimainathan L, Chandrasekar B, Choudhury GG (2003) Phosphatidylinositol 3-kinase regulates bone morphogenetic protein-2 (BMP-2)-induced myocyte enhancer factor 2A-dependent transcription of BMP-2 gene in cardiomyocyte precursor cells. J Biol Chem 278: 21998–22005

    Article  CAS  Google Scholar 

  87. Ghosh-Choudhury N, Abboud SL, Chandrasekar B, Ghosh Choudhury G (2003) BMP-2 regulates cardiomyocyte contractility in a phosphatidylinositol 3 kinase-dependent manner. FEBS Lett 544: 181–184

    Article  CAS  Google Scholar 

  88. Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95: 29–39

    Article  CAS  Google Scholar 

  89. Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273: 13375–13378

    Article  CAS  Google Scholar 

  90. Ford-Hutchinson AF, Ali Z, Lines SE, Hallgrimsson B, Boyd SK, Jirik FR (2007) Inactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnormalities and skeletal overgrowth. J Bone Miner Res 22: 1245–1259

    Article  CAS  Google Scholar 

  91. Liu X, Bruxvoort KJ, Zylstra CR, Liu J, Cichowski R, Faugere MC, Bouxsein ML, Wan C, Williams BO, Clemens TL (2007) Lifelong accumulation of bone in mice lacking Pten in osteoblasts. Proc Natl Acad Sci USA 104: 2259–2264

    Article  CAS  Google Scholar 

  92. Ghosh-Choudhury N, Mandal CC, Choudhury GG (2007) Statin-induced Ras activation integrates the phosphatidylinositol 3-kinase signal to Akt and MAPK for bone morphogenetic protein-2 expression in osteoblast differentiation. J Biol Chem 282: 4983–4993

    Article  CAS  Google Scholar 

  93. Ghosh-Choudhury N, Singha PK, Woodruff K, St Clair P, Bsoul S, Werner SL, Choudhury GG (2006) Concerted action of Smad and CREB-binding protein regulates bone morphogenetic protein-2-stimulated osteoblastic colony-stimulating factor-1 expression. J Biol Chem 281: 20160–20170

    Article  CAS  Google Scholar 

  94. Ghosh Choudhury G, Jin DC, Kim Y, Celeste A, Ghosh-Choudhury N, Abboud HE (1999) Bone morphogenetic protein-2 inhibits MAPK-dependent Elk-1 transactivation and DNA synthesis induced by EGF in mesangial cells. Biochem Biophys Res Commun 258: 490–496

    Article  CAS  Google Scholar 

  95. Ghosh Choudhury G, Kim YS, Simon M, Wozney J, Harris S, Ghosh-Choudhury N, Abboud HE (1999) Bone morphogenetic protein 2 inhibits platelet-derived growth factor-induced c-fos gene transcription and DNA synthesis in mesangial cells. Involvement of mitogen-activated protein kinase. J Biol Chem 274: 10897–10902

    Article  CAS  Google Scholar 

  96. Ghosh-Choudhury N, Ghosh-Choudhury G, Celeste A, Ghosh PM, Moyer M, Abboud SL, Kreisberg J (2000) Bone morphogenetic protein-2 induces cyclin kinase inhibitor p21 and hypophosphorylation of retinoblastoma protein in estradiol-treated MCF-7 human breast cancer cells. Biochim Biophys Acta 1497: 186–196

    Article  CAS  Google Scholar 

  97. Ghosh-Choudhury N, Woodruff K, Qi W, Celeste A, Abboud SL, Ghosh Choudhury G (2000) Bone morphogenetic protein-2 blocks MDA MB 231 human breast cancer cell proliferation by inhibiting cyclin-dependent kinase-mediated retinoblastoma protein phosphorylation. Biochem Biophys Res Commun 272: 705–711

    Article  CAS  Google Scholar 

  98. Ide H, Yoshida T, Matsumoto N, Aoki K, Osada Y, Sugimura T, Terada M (1997) Growth regulation of human prostate cancer cells by bone morphogenetic protein-2. Cancer Res 57: 5022–5027

    CAS  Google Scholar 

  99. Kim IY, Lee DH, Lee DK, Ahn HJ, Kim MM, Kim SJ, Morton RA (2004) Loss of expression of bone morphogenetic protein receptor type II in human prostate cancer cells. Oncogene 23: 7651–7659

    Article  CAS  Google Scholar 

  100. Miyazaki H, Watabe T, Kitamura T, Miyazono K (2004) BMP signals inhibit proliferation and in vivo tumor growth of androgen-insensitive prostate carcinoma cells. Oncogene 23: 9326–9335

    Article  CAS  Google Scholar 

  101. Brubaker KD, Corey E, Brown LG, Vessella RL (2004) Bone morphogenetic protein signaling in prostate cancer cell lines. J Cell Biochem 91: 151–160

    Article  CAS  Google Scholar 

  102. Tomari K, Kumagai T, Shimizu T, Takeda K (2005) Bone morphogenetic protein-2 induces hypophosphorylation of Rb protein and repression of E2F in androgen-treated LNCaP human prostate cancer cells. Int J Mol Med 15: 253–258

    CAS  Google Scholar 

  103. Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH et al (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271: 350–353

    Article  CAS  Google Scholar 

  104. Miyaki M, Iijima T, Konishi M, Sakai K, Ishii A, Yasuno M, Hishima T, Koike M, Shitara N, Iwama T et al (1999) Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene 18: 3098–3103

    Article  CAS  Google Scholar 

  105. Buijs JT, Rentsch CA, van der Horst G, van Overveld PG, Wetterwald A, Schwaninger R, Henriquez NV, Ten Dijke P, Borovecki F, Markwalder R et al (2007) BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo. Am J Pathol 171: 1047–1057

    Article  CAS  Google Scholar 

  106. Sugimori K, Matsui K, Motomura H, Tokoro T, Wang J, Higa S, Kimura T, Kitajima I (2005) BMP-2 prevents apoptosis of the N1511 chondrocytic cell line through PI3K/ Akt-mediated NF-kappaB activation. J Bone Miner Metab 23: 411–419

    Article  CAS  Google Scholar 

  107. Feng JQ, Xing L, Zhang JH, Zhao M, Horn D, Chan J, Boyce BF, Harris SE, Mundy GR, Chen D (2003) NF-kappaB specifically activates BMP-2 gene expression in growth plate chondrocytes in vivo and in a chondrocyte cell line in vitro. J Biol Chem 278: 29130–29135

    Article  CAS  Google Scholar 

  108. Ghosh-Choudhury N, Choudhury GG, Harris MA, Wozney J, Mundy GR, Abboud SL, Harris SE (2001) Autoregulation of mouse BMP-2 gene transcription is directed by the proximal promoter element. Biochem Biophys Res Commun 286: 101–108

    Article  CAS  Google Scholar 

  109. Kon A, Vindevoghel L, Kouba DJ, Fujimura Y, Uitto J, Mauviel A (1999) Cooperation between SMAD and NF-kappaB in growth factor regulated type VII collagen gene expression. Oncogene 18: 1837–1844

    Article  CAS  Google Scholar 

  110. Lopez-Rovira T, Chalaux E, Rosa JL, Bartrons R, Ventura F (2000) Interaction and functional cooperation of NF-kappa B with Smads. Transcriptional regulation of the junB promoter. J Biol Chem 275: 28937–28946

    Article  CAS  Google Scholar 

  111. Chen LF, Greene WC (2003) Regulation of distinct biological activities of the NF-kappaB transcription factor complex by acetylation. J Mol Med 81: 549–557

    Article  CAS  Google Scholar 

  112. Simonsson M, Kanduri M, Gronroos E, Heldin CH, Ericsson J (2006) The DNA binding activities of Smad2 and Smad3 are regulated by coactivator-mediated acetylation. J Biol Chem 281: 39870–39880

    Article  CAS  Google Scholar 

  113. Inoue Y, Itoh Y, Abe K, Okamoto T, Daitoku H, Fukamizu A, Onozaki K, Hayashi H (2007) Smad3 is acetylated by p300/CBP to regulate its transactivation activity. Oncogene 26: 500–508

    Article  CAS  Google Scholar 

  114. Tu AW, Luo K (2007) Acetylation of Smad2 by the co-activator p300 regulates activin and transforming growth factor beta response. J Biol Chem 282: 21187–21196

    Article  CAS  Google Scholar 

  115. Das F, Ghosh-Choudhury N, Venkatesan B, Li X, Mahimainathan L, Choudhury GG (2007) Akt kinase targets association of CBP with SMAD 3 to regulate TGFbetainduced expression of plasminogen activator inhibitor-1. J Cell Physiol 214: 513–527

    Article  CAS  Google Scholar 

  116. Xu J, Rogers MB (2007) Modulation of bone morphogenetic protein (BMP) 2 gene expression by Sp1 transcription factors. Gene 392: 221–229

    Article  CAS  Google Scholar 

  117. Ohyama K, Chung CH, Chen E, Gibson CW, Misof K, Fratzl P, Shapiro IM (1997) p53 influences mice skeletal development. J Craniofac Genet Dev Biol 17: 161–171

    CAS  Google Scholar 

  118. Ghosh-Choudhury N, Harris MA, Wozney J, Mundy GR, Harris SE (1997) Clonal osteoblastic cell lines from p53 null mouse calvariae are immortalized and dependent on bone morphogenetic protein 2 for mature osteoblastic phenotype. Biochem Biophys Res Commun 231: 196–202

    Article  CAS  Google Scholar 

  119. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M et al (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89: 755–764

    Article  CAS  Google Scholar 

  120. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B(2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108: 17–29

    Article  CAS  Google Scholar 

  121. 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: 8783–8792

    Article  CAS  Google Scholar 

  122. Lee MH, Javed A, Kim HJ, Shin HI, Gutierrez S, Choi JY, Rosen V, Stein JL, van Wijnen AJ, Stein GS et al (1999) Transient upregulation of CBFA1 in response to bone morphogenetic protein-2 and transforming growth factor beta1 in C2C12 myogenic cells coincides with suppression of the myogenic phenotype but is not sufficient for osteoblast differentiation. J Cell Biochem 73: 114–125

    Article  CAS  Google Scholar 

  123. Ryoo HM, Lee MH, Kim YJ (2006) Critical molecular switches involved in BMP-2-induced osteogenic differentiation of mesenchymal cells. Gene 366: 51–57

    Article  CAS  Google Scholar 

  124. Rajan P, Panchision DM, Newell LF, McKay RD (2003) BMPs signal alternately through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells. J Cell Biol 161: 911–921

    Article  CAS  Google Scholar 

  125. Fukuda S, Abematsu M, Mori H, Yanagisawa M, Kagawa T, Nakashima K, Yoshimura A, Taga T (2007) Potentiation of astrogliogenesis by STAT3-mediated activation of bone morphogenetic protein-Smad signaling in neural stem cells. Mol Cell Biol 27: 4931–4937

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. South Texas Veterans Health Care System and Departments of Pathology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Nandini Ghosh-Choudhury

  2. Departments of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Goutam Ghosh-Choudhury

Authors
  1. Nandini Ghosh-Choudhury
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Goutam Ghosh-Choudhury
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. School of Medicine Inst. Anatomy Drago Perovic, University of Zagreb, Salata 11, 10000, Zagreb, Croatia

    Slobodan Vukicevic

  2. Genzyme Corporation, One Mountain Road, Framingham, MA, 01701-9322, USA

    Kuber T. Sampath

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Birkhäuser Verlag Basel/Switzerland

About this chapter

Cite this chapter

Ghosh-Choudhury, N., Ghosh-Choudhury, G. (2008). Signaling cross-talk by bone morphogenetic proteins. In: Vukicevic, S., Sampath, K.T. (eds) Bone Morphogenetic Proteins: From Local to Systemic Therapeutics. Progress in Inflammation Research. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8552-1_9

Download citation

  • DOI: https://doi.org/10.1007/978-3-7643-8552-1_9

  • Publisher Name: Birkhäuser Basel

  • Print ISBN: 978-3-7643-8551-4

  • Online ISBN: 978-3-7643-8552-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation