Development - BMP signaling

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BMP signaling

Bone morphogenetic proteins (BMPs) are the members of the transforming growth factor-beta superfamily of secreted signaling molecules [1]. BMPs transduce their signals via two signaling pathways: SMAD-dependent pathway, the so called "canonical" BMP pathway, and SMAD-independent BMP/MAPK cascade [2].

Transduction of BMP signal involves two types of transmembrane serine/threonine kinase receptors: type I and type II. Bone morphogenetic protein 2, 4, 6 and 7 (BMP2, BMP4, BMP6 and BMP7) can bind to three type I receptors: Bone morphogenetic protein receptor, type IA (BMPR1A), Bone morphogenetic protein receptor, type IB (BMPR1B) and Activin A receptor, type I (ALK-2) [1], [3], [4], [5], [6], and one type II receptor, Bone morphogenetic protein receptor type II (BMP receptor 2) [6], [7], [8].

After ligand binding, BMP receptor 2 recruits and phosphorylates BMPR1A, BMPR1B and ALK-2, resulting in the formation of heteromeric ligand/receptor complex. Activated BMPR1A, BMPR1B and ALK-2 receptors then phosphorylate an appropriate member of Mothers against decapentaplegic (SMAD) protein family - SMAD family members 1, 5 and 9 (SMAD1, SMAD5 and SMAD9 (SMAD8)), called receptor-regulated SMADs (R-SMADs), to elicit cellular responses. Upon phosphorylation, R-SMADs are released from receptors and interact with SMAD family member 4 (SMAD4). SMAD4/R-SMAD heteromeric complexes are then translocated into the nucleus, where SMAD1, SMAD5 and SMAD9 (SMAD8) activate expression of target genes [2].

R-SMADs activate transcription of target genes via cooperation with other transcription factors or via complex formation with general transcriptional coactivators CREB binding protein (CBP) and E1A binding protein p300 (p300) [9], [10]. BMP-activated SMAD1 interacts with CBP and p300, and, then, SMAD1 and p300 / CBP synergistically activate gene expression [11]. SMAD5 and SMAD9 (SMAD8) can also form complexes with CBP [12], [13]. The interaction of R-SMADs with CBP, activated by cAMP responsive element binding protein 1 (CREB1), results in enhanced transcriptional activity of R-SMADs [13].

Extracellularly, the activity of BMPs can be regulated by secreted antagonists, such as Chordin, Noggin, Gremlin 1, cysteine knot superfamily, homolog (Gremlin), Cerberus 1, cysteine knot superfamily, homolog (Cerberus), and Follistatin [14].

BMP/ SMAD signaling is also regulated by a variety of intracellular molecules [2]. The inhibitory SMADs, SMAD family member 6 and 7 (SMAD6 and SMAD7), can interact with activated type I BMP receptors, and, thereby, suppress BMP signaling [2]. Thus, SMAD6 binds to BMPR1B and inhibits downstream phosphorylation of SMAD1 and SMAD5 [15]. Moreover, SMAD6 binds to SMAD1 and prevents the formation of SMAD4/SMAD1 complex [16]. SMAD7 can bind to BMPR1A, BMPR1B and ALK-2 and inhibit downstream phosphorylation of SMAD1 and SMAD5 [17], [18].

SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) induces ubiquitination and proteasomal degradation of SMAD1, SMAD5 [19] and BMPR1B [20]. SMAD6 and SMAD7 can form the complex with SMURF1. This interaction enhances degradation of SMAD1 and SMAD5, and as well promotes SMURF1 recruitment to BMPR1B and subsequent BMPR1B ubiquitination [20]. SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2) can target SMAD1 for degradation [21].

V-ski sarcoma viral oncogene homolog (Ski) interacts with SMAD1, SMAD5 and SMAD4, thus repressing BMP signaling [22], [23]. TOB1 transducer of ERBB2, 1 (Tob1), the member of anti-proliferative protein family, can directly interact with SMAD1, SMAD5 and SMAD9 (SMAD8), followed by repression of BMP/SMAD-dependent transcription and, as a consequence, osteogenesis [24]. Another way for Tob1 inhibitory action is modulating the function of SMAD6 and SMAD7, and enhancing the interaction between SMAD6 and BMPR1B [25].

The alternative BMP-induced pathway involves stimulation of mitogen-activated protein kinases (MAPK). BMPR1A binds to X-linked inhibitor of apoptosis (XIAP), which, in turn, recruits TGF-beta activated kinase 1/MAP3K7 binding protein 1 (TAB1). TAB1 activates Mitogen-activated protein kinase kinase kinase 7 (TAK1) downstream of BMP2, BMP4 and BMPR1A [26], [27], [28], [29]. TAK1 then phosphorylates Mitogen-activated protein kinase kinase 3 and 6 (MEK3 and MEK6), leading to activation of Mitogen-activated protein kinase 14 (p38 MAPK) and subsequent stimulation of Activating transcription factor 2 (ATF-2) [30], [31]. BMP-induced ATF-2 activation results in stem cell differentiation [32], [33].

SMAD6 binds to TAK1 and inhibits its activity, representing crosstalk between BMP/SMAD and BMP/MAPK pathways. This interaction leads to blockage of BMP2-induced p38 MAPK-mediated apoptosis [34].

References:

  1. Chen D, Zhao M, Mundy GR
    Bone morphogenetic proteins. Growth factors (Chur, Switzerland) 2004 Dec;22(4):233-41
  2. von Bubnoff A, Cho KW
    Intracellular BMP signaling regulation in vertebrates: pathway or network? Developmental biology 2001 Nov 1;239(1):1-14
  3. Yamaji N, Celeste AJ, Thies RS, Song JJ, Bernier SM, Goltzman D, Lyons KM, Nove J, Rosen V, Wozney JM
    A mammalian serine/threonine kinase receptor specifically binds BMP-2 and BMP-4. Biochemical and biophysical research communications 1994 Dec 30;205(3):1944-51
  4. ten Dijke P, Yamashita H, Sampath TK, Reddi AH, Estevez M, Riddle DL, Ichijo H, Heldin CH, Miyazono K
    Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. The Journal of biological chemistry 1994 Jun 24;269(25):16985-8
  5. Koenig BB, Cook JS, Wolsing DH, Ting J, Tiesman JP, Correa PE, Olson CA, Pecquet AL, Ventura F, Grant RA
    Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells. Molecular and cellular biology 1994 Sep;14(9):5961-74
  6. Ebisawa T, Tada K, Kitajima I, Tojo K, Sampath TK, Kawabata M, Miyazono K, Imamura T
    Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation. Journal of cell science 1999 Oct;112 ( Pt 20):3519-27
  7. Rosenzweig BL, Imamura T, Okadome T, Cox GN, Yamashita H, ten Dijke P, Heldin CH, Miyazono K
    Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proceedings of the National Academy of Sciences of the United States of America 1995 Aug 15;92(17):7632-6
  8. Liu F, Ventura F, Doody J, Massagué J
    Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Molecular and cellular biology 1995 Jul;15(7):3479-86
  9. Derynck R, Zhang YE
    Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003 Oct 9;425(6958):577-84
  10. Ross S, Hill CS
    How the Smads regulate transcription. The international journal of biochemistry & cell biology 2008;40(3):383-408
  11. Pearson KL, Hunter T, Janknecht R
    Activation of Smad1-mediated transcription by p300/CBP. Biochimica et biophysica acta 1999 Dec 23;1489(2-3):354-64
  12. Ghosh-Choudhury N, Singha PK, Woodruff K, St Clair P, Bsoul S, Werner SL, Choudhury GG
    Concerted action of Smad and CREB-binding protein regulates bone morphogenetic protein-2-stimulated osteoblastic colony-stimulating factor-1 expression. The Journal of biological chemistry 2006 Jul 21;281(29):20160-70
  13. Ohta Y, Nakagawa K, Imai Y, Katagiri T, Koike T, Takaoka K
    Cyclic AMP enhances Smad-mediated BMP signaling through PKA-CREB pathway. Journal of bone and mineral metabolism 2008;26(5):478-84
  14. Balemans W, Van Hul W
    Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. Developmental biology 2002 Oct 15;250(2):231-50
  15. Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M, Miyazono K
    Smad6 inhibits signalling by the TGF-beta superfamily. Nature 1997 Oct 9;389(6651):622-6
  16. Hata A, Lagna G, Massagué J, Hemmati-Brivanlou A
    Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes & development 1998 Jan 15;12(2):186-97
  17. Souchelnytskyi S, Nakayama T, Nakao A, Morén A, Heldin CH, Christian JL, ten Dijke P
    Physical and functional interaction of murine and Xenopus Smad7 with bone morphogenetic protein receptors and transforming growth factor-beta receptors. The Journal of biological chemistry 1998 Sep 25;273(39):25364-70
  18. Mochizuki T, Miyazaki H, Hara T, Furuya T, Imamura T, Watabe T, Miyazono K
    Roles for the MH2 domain of Smad7 in the specific inhibition of transforming growth factor-beta superfamily signaling. The Journal of biological chemistry 2004 Jul 23;279(30):31568-74
  19. Zhu H, Kavsak P, Abdollah S, Wrana JL, Thomsen GH
    A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 1999 Aug 12;400(6745):687-93
  20. Murakami G, Watabe T, Takaoka K, Miyazono K, Imamura T
    Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Molecular biology of the cell 2003 Jul;14(7):2809-17
  21. Zhang Y, Chang C, Gehling DJ, Hemmati-Brivanlou A, Derynck R
    Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proceedings of the National Academy of Sciences of the United States of America 2001 Jan 30;98(3):974-9
  22. Wang W, Mariani FV, Harland RM, Luo K
    Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 2000 Dec 19;97(26):14394-9
  23. Luo K
    Negative regulation of BMP signaling by the ski oncoprotein. The Journal of bone and joint surgery. American volume 2003;85-A Suppl 3:39-43
  24. Yoshida Y, Tanaka S, Umemori H, Minowa O, Usui M, Ikematsu N, Hosoda E, Imamura T, Kuno J, Yamashita T, Miyazono K, Noda M, Noda T, Yamamoto T
    Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 2000 Dec 22;103(7):1085-97
  25. Yoshida Y, von Bubnoff A, Ikematsu N, Blitz IL, Tsuzuku JK, Yoshida EH, Umemori H, Miyazono K, Yamamoto T, Cho KW
    Tob proteins enhance inhibitory Smad-receptor interactions to repress BMP signaling. Mechanisms of development 2003 May;120(5):629-37
  26. Shibuya H, Yamaguchi K, Shirakabe K, Tonegawa A, Gotoh Y, Ueno N, Irie K, Nishida E, Matsumoto K
    TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction. Science (New York, N.Y.) 1996 May 24;272(5265):1179-82
  27. Shibuya H, Iwata H, Masuyama N, Gotoh Y, Yamaguchi K, Irie K, Matsumoto K, Nishida E, Ueno N
    Role of TAK1 and TAB1 in BMP signaling in early Xenopus development. The EMBO journal 1998 Feb 16;17(4):1019-28
  28. Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K, Ueno N, Nishida E, Shibuya H, Matsumoto K
    XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. The EMBO journal 1999 Jan 4;18(1):179-87
  29. Ono K, Ohtomo T, Sato S, Sugamata Y, Suzuki M, Hisamoto N, Ninomiya-Tsuji J, Tsuchiya M, Matsumoto K
    An evolutionarily conserved motif in the TAB1 C-terminal region is necessary for interaction with and activation of TAK1 MAPKKK. The Journal of biological chemistry 2001 Jun 29;276(26):24396-400
  30. Moriguchi T, Kuroyanagi N, Yamaguchi K, Gotoh Y, Irie K, Kano T, Shirakabe K, Muro Y, Shibuya H, Matsumoto K, Nishida E, Hagiwara M
    A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. The Journal of biological chemistry 1996 Jun 7;271(23):13675-9
  31. Iwasaki S, Iguchi M, Watanabe K, Hoshino R, Tsujimoto M, Kohno M
    Specific activation of the p38 mitogen-activated protein kinase signaling pathway and induction of neurite outgrowth in PC12 cells by bone morphogenetic protein-2. The Journal of biological chemistry 1999 Sep 10;274(37):26503-10
  32. Monzen K, Hiroi Y, Kudoh S, Akazawa H, Oka T, Takimoto E, Hayashi D, Hosoda T, Kawabata M, Miyazono K, Ishii S, Yazaki Y, Nagai R, Komuro I
    Smads, TAK1, and their common target ATF-2 play a critical role in cardiomyocyte differentiation. The Journal of cell biology 2001 May 14;153(4):687-98
  33. Cao W, Daniel KW, Robidoux J, Puigserver P, Medvedev AV, Bai X, Floering LM, Spiegelman BM, Collins S
    p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Molecular and cellular biology 2004 Apr;24(7):3057-67
  34. Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T
    BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. The Journal of biological chemistry 2000 Jun 9;275(23):17647-52

  1. Chen D, Zhao M, Mundy GR
    Bone morphogenetic proteins. Growth factors (Chur, Switzerland) 2004 Dec;22(4):233-41
  2. von Bubnoff A, Cho KW
    Intracellular BMP signaling regulation in vertebrates: pathway or network? Developmental biology 2001 Nov 1;239(1):1-14
  3. Yamaji N, Celeste AJ, Thies RS, Song JJ, Bernier SM, Goltzman D, Lyons KM, Nove J, Rosen V, Wozney JM
    A mammalian serine/threonine kinase receptor specifically binds BMP-2 and BMP-4. Biochemical and biophysical research communications 1994 Dec 30;205(3):1944-51
  4. ten Dijke P, Yamashita H, Sampath TK, Reddi AH, Estevez M, Riddle DL, Ichijo H, Heldin CH, Miyazono K
    Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. The Journal of biological chemistry 1994 Jun 24;269(25):16985-8
  5. Koenig BB, Cook JS, Wolsing DH, Ting J, Tiesman JP, Correa PE, Olson CA, Pecquet AL, Ventura F, Grant RA
    Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells. Molecular and cellular biology 1994 Sep;14(9):5961-74
  6. Ebisawa T, Tada K, Kitajima I, Tojo K, Sampath TK, Kawabata M, Miyazono K, Imamura T
    Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation. Journal of cell science 1999 Oct;112 ( Pt 20):3519-27
  7. Rosenzweig BL, Imamura T, Okadome T, Cox GN, Yamashita H, ten Dijke P, Heldin CH, Miyazono K
    Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proceedings of the National Academy of Sciences of the United States of America 1995 Aug 15;92(17):7632-6
  8. Liu F, Ventura F, Doody J, Massagué J
    Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Molecular and cellular biology 1995 Jul;15(7):3479-86
  9. Derynck R, Zhang YE
    Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003 Oct 9;425(6958):577-84
  10. Ross S, Hill CS
    How the Smads regulate transcription. The international journal of biochemistry & cell biology 2008;40(3):383-408
  11. Pearson KL, Hunter T, Janknecht R
    Activation of Smad1-mediated transcription by p300/CBP. Biochimica et biophysica acta 1999 Dec 23;1489(2-3):354-64
  12. Ghosh-Choudhury N, Singha PK, Woodruff K, St Clair P, Bsoul S, Werner SL, Choudhury GG
    Concerted action of Smad and CREB-binding protein regulates bone morphogenetic protein-2-stimulated osteoblastic colony-stimulating factor-1 expression. The Journal of biological chemistry 2006 Jul 21;281(29):20160-70
  13. Ohta Y, Nakagawa K, Imai Y, Katagiri T, Koike T, Takaoka K
    Cyclic AMP enhances Smad-mediated BMP signaling through PKA-CREB pathway. Journal of bone and mineral metabolism 2008;26(5):478-84
  14. Balemans W, Van Hul W
    Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. Developmental biology 2002 Oct 15;250(2):231-50
  15. Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M, Miyazono K
    Smad6 inhibits signalling by the TGF-beta superfamily. Nature 1997 Oct 9;389(6651):622-6
  16. Hata A, Lagna G, Massagué J, Hemmati-Brivanlou A
    Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes & development 1998 Jan 15;12(2):186-97
  17. Souchelnytskyi S, Nakayama T, Nakao A, Morén A, Heldin CH, Christian JL, ten Dijke P
    Physical and functional interaction of murine and Xenopus Smad7 with bone morphogenetic protein receptors and transforming growth factor-beta receptors. The Journal of biological chemistry 1998 Sep 25;273(39):25364-70
  18. Mochizuki T, Miyazaki H, Hara T, Furuya T, Imamura T, Watabe T, Miyazono K
    Roles for the MH2 domain of Smad7 in the specific inhibition of transforming growth factor-beta superfamily signaling. The Journal of biological chemistry 2004 Jul 23;279(30):31568-74
  19. Zhu H, Kavsak P, Abdollah S, Wrana JL, Thomsen GH
    A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 1999 Aug 12;400(6745):687-93
  20. Murakami G, Watabe T, Takaoka K, Miyazono K, Imamura T
    Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Molecular biology of the cell 2003 Jul;14(7):2809-17
  21. Zhang Y, Chang C, Gehling DJ, Hemmati-Brivanlou A, Derynck R
    Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proceedings of the National Academy of Sciences of the United States of America 2001 Jan 30;98(3):974-9
  22. Wang W, Mariani FV, Harland RM, Luo K
    Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 2000 Dec 19;97(26):14394-9
  23. Luo K
    Negative regulation of BMP signaling by the ski oncoprotein. The Journal of bone and joint surgery. American volume 2003;85-A Suppl 3:39-43
  24. Yoshida Y, Tanaka S, Umemori H, Minowa O, Usui M, Ikematsu N, Hosoda E, Imamura T, Kuno J, Yamashita T, Miyazono K, Noda M, Noda T, Yamamoto T
    Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 2000 Dec 22;103(7):1085-97
  25. Yoshida Y, von Bubnoff A, Ikematsu N, Blitz IL, Tsuzuku JK, Yoshida EH, Umemori H, Miyazono K, Yamamoto T, Cho KW
    Tob proteins enhance inhibitory Smad-receptor interactions to repress BMP signaling. Mechanisms of development 2003 May;120(5):629-37
  26. Shibuya H, Yamaguchi K, Shirakabe K, Tonegawa A, Gotoh Y, Ueno N, Irie K, Nishida E, Matsumoto K
    TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction. Science (New York, N.Y.) 1996 May 24;272(5265):1179-82
  27. Shibuya H, Iwata H, Masuyama N, Gotoh Y, Yamaguchi K, Irie K, Matsumoto K, Nishida E, Ueno N
    Role of TAK1 and TAB1 in BMP signaling in early Xenopus development. The EMBO journal 1998 Feb 16;17(4):1019-28
  28. Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K, Ueno N, Nishida E, Shibuya H, Matsumoto K
    XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. The EMBO journal 1999 Jan 4;18(1):179-87
  29. Ono K, Ohtomo T, Sato S, Sugamata Y, Suzuki M, Hisamoto N, Ninomiya-Tsuji J, Tsuchiya M, Matsumoto K
    An evolutionarily conserved motif in the TAB1 C-terminal region is necessary for interaction with and activation of TAK1 MAPKKK. The Journal of biological chemistry 2001 Jun 29;276(26):24396-400
  30. Moriguchi T, Kuroyanagi N, Yamaguchi K, Gotoh Y, Irie K, Kano T, Shirakabe K, Muro Y, Shibuya H, Matsumoto K, Nishida E, Hagiwara M
    A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. The Journal of biological chemistry 1996 Jun 7;271(23):13675-9
  31. Iwasaki S, Iguchi M, Watanabe K, Hoshino R, Tsujimoto M, Kohno M
    Specific activation of the p38 mitogen-activated protein kinase signaling pathway and induction of neurite outgrowth in PC12 cells by bone morphogenetic protein-2. The Journal of biological chemistry 1999 Sep 10;274(37):26503-10
  32. Monzen K, Hiroi Y, Kudoh S, Akazawa H, Oka T, Takimoto E, Hayashi D, Hosoda T, Kawabata M, Miyazono K, Ishii S, Yazaki Y, Nagai R, Komuro I
    Smads, TAK1, and their common target ATF-2 play a critical role in cardiomyocyte differentiation. The Journal of cell biology 2001 May 14;153(4):687-98
  33. Cao W, Daniel KW, Robidoux J, Puigserver P, Medvedev AV, Bai X, Floering LM, Spiegelman BM, Collins S
    p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Molecular and cellular biology 2004 Apr;24(7):3057-67
  34. Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T
    BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. The Journal of biological chemistry 2000 Jun 9;275(23):17647-52

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