Development - FGF-family signaling

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FGF-family signaling

   

Abstract:

   

Fibroblast growth factors (FGFs) have been implicated in  diverse cellular processes including cell survival, differentiation, proliferation and  epithelial-to-mesenchymal transition.

   

FGFs bind to their cognate receptors and activate  c-Raf-1/ ERK1 (MAPK3)/  ERK2 (MAPK1) and Rac1/  p38 MAPK cascades, both of them are involved in regulation  of cell proliferation and differentiation. Activation of PI3K reg class  IA/ PI3K cat class IA/ AKT(PKB) promotes  cells survival and epithelial-to-mesenchymal transition. PLC-gamma  1/ PKCs cascade takes part in regulation of  development and stress response in different tissues.

   

   

Details:

   

Fibroblast growth factors (FGFs) have been implicated in  diverse cellular processes including cell anti-apoptosis, cell differentiation, cell proliferation and epithelial to mesenchymal transition [1], [2].

   

FGFs comprise a family of 23 genes encoding structurally  related proteins [2], [3]. FGFs  mediate their cellular responses by binding to and activating a family of four receptor  tyrosine kinases with designated high affinity for FGFR1, FGFR2,  FGFR3 and FGFR4 [2], [3], [4].

   

FGFs activity and specificity are regulated by heparan  sulfate proteoglycans (such as Perlecan) [5], [6].  Heparin associates with  FGFs and FGFRs to form trimeric  complexes [7], [8], [9].

   

Binding of FGF1, FGF2, FGF3,  FGF4, FGF6, FGF1,  FGF8, FGF9, FGF10,  FGF16 and FGF19 to their cognate receptors FGFR1, FGFR2,  FGFR3 and FGFR4 lead to activation of FRS2/ SHP-2/  GRB2/ SOS/ H-Ras/  c-Raf-1/ MEK1(MAP2K1)/ MEK2(MAP2K2)/  ERK1 (MAPK3)/ ERK2 (MAPK1) cascade, which regulates cell proliferation and  cell differentiation [2], [10], [11], [12]. Furthermore, FGFs can induce  Shc/ GRB2/ SOS complex formation,  resulting in activation of ERK1 (MAPK3)/  ERK2 (MAPK1) and cell proliferation [13], [14], [15], [16]. In  addition, FGFs can activate Rac1/ MLK3(MAP3K11)/  MEK6(MAP2K6)/ p38 MAPK pathway [17], [18], [19] probably via FRS2/  SHP-2/ GRB2/ SOS [2], [11]. Activation of p38 MAPK is also involved in regulation of cell proliferation  and cell differentiation [2], [19], [20].

   

Assembly of FRS2/  SHP-2/ GRB2/ GAB1 complex is induced  by FGFs stimulation that results in activation of  PI3K reg class IA/ PI3K cat class IA/ PtdIns(3,4,5)P3 / AKT(PKB)  pathway. Induction of AKT(PKB) promotes cells  anti-apoptosis and epithelial to mesenchymal transition  [2], [21], [22], [23].

   

FGFs play a critical role in membrane phospholipid  hydrolysis in the cell. Upon binding to FGFR1,  FGFR3, FGFR4, FGFs stimulates cytosolic form of  PLC-gamma 1 [2].  PLC-gamma 1 activation leads to  PtdIns(4,5)P2 hydrolysis and generation of two  second messengers, 1,2-Diacyglycerol and  IP3. IP3 activates IP3 receptor and  accumulation of Ca("2+) in the cytoplasm.  1,2-Diacyglycerol activates  PKC-delta and PKC-epsilon [24], [25]. 1,2-Diacyglycerol and Ca("2+) induce activation of PKC-alpha and PKC-beta [25]. PLC-gamma 1/  PKCs cascade takes part in regulation of developmental process and response to stress in different tissues [2], [25], [26].

         

 

Objects list:

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
         1,2-Diacyglycerol            1,2-Diacyglycerol  Compound group   
         AKT(PKB)           AKT(PKB) Protein group   
         Ca("2+)           Chemical IUPAC name calcium(+2) cation   
         ERK1 (MAPK3)           Mitogen-activated protein kinase 3    
         ERK2 (MAPK1)           Mitogen-activated protein kinase 1    
         FGF1           Heparin-binding growth factor 1    
         FGF10           Fibroblast growth factor 10    
         FGF16           Fibroblast growth factor 16    
         FGF19           Fibroblast growth factor 19    
         FGF2           Heparin-binding growth factor 2    
         FGF3           Fibroblast growth factor 3    
         FGF4           Fibroblast growth factor 4    
         FGF6           Fibroblast growth factor 6    
         FGF8           Fibroblast growth factor 8    
         FGF9           Glia-activating factor    
         FGFR1           Basic fibroblast growth factor receptor 1    
         FGFR2           Fibroblast growth factor receptor 2    
         FGFR3           Fibroblast growth factor receptor 3    
         FGFR4           Fibroblast growth factor receptor 4    
         FRS2           Fibroblast growth factor receptor substrate 2    
         GAB1           GRB2-associated-binding protein 1    
         GRB2           Growth factor receptor-bound protein 2    
         H-Ras           GTPase HRas    
         Heparin            Heparin  Compound group   
         IP3           Chemical IUPAC name [(1R,2S,3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-diphosphonooxycyclohexyl] dihydrogen phosphate   
         IP3 receptor           A family of receptors for the second messenger inositol 1,4,5-trisphosphate (IP3) Protein group   
         MEK1(MAP2K1)           Dual specificity mitogen-activated protein kinase kinase 1    
         MEK2(MAP2K2)           Dual specificity mitogen-activated protein kinase kinase 2    
         MEK6(MAP2K6)           Dual specificity mitogen-activated protein kinase kinase 6    
         MLK3(MAP3K11)           Mitogen-activated protein kinase kinase kinase 11    
         PI3K cat class IA           The catalytic subunit of phosphatidylinositol 3-kinase subgroups  IA Protein group   
         PI3K reg class IA           The regulatory subunit of phosphatidylinositol 3-kinase subgroups  IA Protein group   
         PKC-alpha           Protein kinase C alpha type    
         PKC-beta           Protein kinase C beta type    
         PKC-delta           Protein kinase C delta type    
         PKC-epsilon           Protein kinase C epsilon type    
         PLC-gamma 1           1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-1    
         PtdIns(3,4,5)P3            PtdIns(3,4,5)P3  Compound group   
         PtdIns(4,5)P2            PtdIns(4,5)P2  Compound group   
         Rac1           Ras-related C3 botulinum toxin substrate 1    
         SHP-2           Tyrosine-protein phosphatase non-receptor type 11    
         SOS           SOS Protein group   
         Shc           SHC-transforming protein 1    
         c-Raf-1           RAF proto-oncogene serine/threonine-protein kinase    
   ???????      p38 MAPK           p38 mitogen-activated protein kinase Protein group   

References:

  1. Bottcher RT, Niehrs C
    Fibroblast growth factor signaling during early vertebrate development. Endocrine reviews 2005 Feb;26(1):63-77
  2. Villegas SN, Canham M, Brickman JM
    FGF signalling as a mediator of lineage transitions--evidence from embryonic stem cell differentiation. Journal of cellular biochemistry 2010 May;110(1):10-20
  3. Itoh N, Ornitz DM
    Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. Journal of biochemistry 2011 Feb;149(2):121-30
  4. Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M
    Receptor specificity of the fibroblast growth factor family. The Journal of biological chemistry 1996 Jun 21;271(25):15292-7
  5. Knox S, Merry C, Stringer S, Melrose J, Whitelock J
    Not all perlecans are created equal: interactions with fibroblast growth factor (FGF) 2 and FGF receptors. The Journal of biological chemistry 2002 Apr 26;277(17):14657-65
  6. Knox SM, Whitelock JM
    Perlecan: how does one molecule do so many things? Cellular and molecular life sciences : CMLS 2006 Nov;63(21):2435-45
  7. Presta M, Oreste P, Zoppetti G, Belleri M, Tanghetti E, Leali D, Urbinati C, Bugatti A, Ronca R, Nicoli S, Moroni E, Stabile H, Camozzi M, Hernandez GA, Mitola S, Dell'Era P, Rusnati M, Ribatti D
    Antiangiogenic activity of semisynthetic biotechnological heparins: low-molecular-weight-sulfated Escherichia coli K5 polysaccharide derivatives as fibroblast growth factor antagonists. Arteriosclerosis, thrombosis, and vascular biology 2005 Jan;25(1):71-6
  8. Harmer NJ, Ilag LL, Mulloy B, Pellegrini L, Robinson CV, Blundell TL
    Towards a resolution of the stoichiometry of the fibroblast growth factor (FGF)-FGF receptor-heparin complex. Journal of molecular biology 2004 Jun 11;339(4):821-34
  9. Asada M, Shinomiya M, Suzuki M, Honda E, Sugimoto R, Ikekita M, Imamura T
    Glycosaminoglycan affinity of the complete fibroblast growth factor family. Biochimica et biophysica acta 2009 Jan 1;1790(1):40-8
  10. Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, Schlessinger J
    A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 1997 May 30;89(5):693-702
  11. Dailey L, Ambrosetti D, Mansukhani A, Basilico C
    Mechanisms underlying differential responses to FGF signaling. Cytokine & growth factor reviews 2005 Apr;16(2):233-47
  12. Gotoh N
    Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer science 2008 Jul;99(7):1319-25
  13. Curto M, Frankel P, Carrero A, Foster DA
    Novel recruitment of Shc, Grb2, and Sos by fibroblast growth factor receptor-1 in v-Src-transformed cells. Biochemical and biophysical research communications 1998 Feb 13;243(2):555-60
  14. Dell'Era P, Mohammadi M, Presta M
    Different tyrosine autophosphorylation requirements in fibroblast growth factor receptor-1 mediate urokinase-type plasminogen activator induction and mitogenesis. Molecular biology of the cell 1999 Jan;10(1):23-33
  15. Raffioni S, Thomas D, Foehr ED, Thompson LM, Bradshaw RA
    Comparison of the intracellular signaling responses by three chimeric fibroblast growth factor receptors in PC12 cells. Proceedings of the National Academy of Sciences of the United States of America 1999 Jun 22;96(13):7178-83
  16. Sakaguchi K, Lorenzi MV, Matsushita H, Miki T
    Identification of a novel activated form of the keratinocyte growth factor receptor by expression cloning from parathyroid adenoma tissue. Oncogene 1999 Sep 30;18(40):5497-505
  17. Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ
    FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. The EMBO journal 1996 Sep 2;15(17):4629-42
  18. Matsumoto T, Turesson I, Book M, Gerwins P, Claesson-Welsh L
    p38 MAP kinase negatively regulates endothelial cell survival, proliferation, and differentiation in FGF-2-stimulated angiogenesis. The Journal of cell biology 2002 Jan 7;156(1):149-60
  19. Raucci A, Laplantine E, Mansukhani A, Basilico C
    Activation of the ERK1/2 and p38 mitogen-activated protein kinase pathways mediates fibroblast growth factor-induced growth arrest of chondrocytes. The Journal of biological chemistry 2004 Jan 16;279(3):1747-56
  20. Maher P
    p38 mitogen-activated protein kinase activation is required for fibroblast growth factor-2-stimulated cell proliferation but not differentiation. The Journal of biological chemistry 1999 Jun 18;274(25):17491-8
  21. Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I
    Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proceedings of the National Academy of Sciences of the United States of America 2001 May 22;98(11):6074-9
  22. Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Muller GA, Neilson EG
    Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney international 2002 May;61(5):1714-28
  23. Lamothe B, Yamada M, Schaeper U, Birchmeier W, Lax I, Schlessinger J
    The docking protein Gab1 is an essential component of an indirect mechanism for fibroblast growth factor stimulation of the phosphatidylinositol 3-kinase/Akt antiapoptotic pathway. Molecular and cellular biology 2004 Jul;24(13):5657-66
  24. Kim HJ, Kim JH, Bae SC, Choi JY, Kim HJ, Ryoo HM
    The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2. The Journal of biological chemistry 2003 Jan 3;278(1):319-26
  25. Tang CH, Yang RS, Huang TH, Liu SH, Fu WM
    Enhancement of fibronectin fibrillogenesis and bone formation by basic fibroblast growth factor via protein kinase C-dependent pathway in rat osteoblasts. Molecular pharmacology 2004 Sep;66(3):440-9
  26. Haimovitz-Friedman A, Balaban N, McLoughlin M, Ehleiter D, Michaeli J, Vlodavsky I, Fuks Z
    Protein kinase C mediates basic fibroblast growth factor protection of endothelial cells against radiation-induced apoptosis. Cancer research 1994 May 15;54(10):2591-7

  1. Bottcher RT, Niehrs C
    Fibroblast growth factor signaling during early vertebrate development. Endocrine reviews 2005 Feb;26(1):63-77
  2. Villegas SN, Canham M, Brickman JM
    FGF signalling as a mediator of lineage transitions--evidence from embryonic stem cell differentiation. Journal of cellular biochemistry 2010 May;110(1):10-20
  3. Itoh N, Ornitz DM
    Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. Journal of biochemistry 2011 Feb;149(2):121-30
  4. Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M
    Receptor specificity of the fibroblast growth factor family. The Journal of biological chemistry 1996 Jun 21;271(25):15292-7
  5. Knox S, Merry C, Stringer S, Melrose J, Whitelock J
    Not all perlecans are created equal: interactions with fibroblast growth factor (FGF) 2 and FGF receptors. The Journal of biological chemistry 2002 Apr 26;277(17):14657-65
  6. Knox SM, Whitelock JM
    Perlecan: how does one molecule do so many things? Cellular and molecular life sciences : CMLS 2006 Nov;63(21):2435-45
  7. Presta M, Oreste P, Zoppetti G, Belleri M, Tanghetti E, Leali D, Urbinati C, Bugatti A, Ronca R, Nicoli S, Moroni E, Stabile H, Camozzi M, Hernandez GA, Mitola S, Dell'Era P, Rusnati M, Ribatti D
    Antiangiogenic activity of semisynthetic biotechnological heparins: low-molecular-weight-sulfated Escherichia coli K5 polysaccharide derivatives as fibroblast growth factor antagonists. Arteriosclerosis, thrombosis, and vascular biology 2005 Jan;25(1):71-6
  8. Harmer NJ, Ilag LL, Mulloy B, Pellegrini L, Robinson CV, Blundell TL
    Towards a resolution of the stoichiometry of the fibroblast growth factor (FGF)-FGF receptor-heparin complex. Journal of molecular biology 2004 Jun 11;339(4):821-34
  9. Asada M, Shinomiya M, Suzuki M, Honda E, Sugimoto R, Ikekita M, Imamura T
    Glycosaminoglycan affinity of the complete fibroblast growth factor family. Biochimica et biophysica acta 2009 Jan 1;1790(1):40-8
  10. Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, Schlessinger J
    A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 1997 May 30;89(5):693-702
  11. Dailey L, Ambrosetti D, Mansukhani A, Basilico C
    Mechanisms underlying differential responses to FGF signaling. Cytokine & growth factor reviews 2005 Apr;16(2):233-47
  12. Gotoh N
    Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer science 2008 Jul;99(7):1319-25
  13. Curto M, Frankel P, Carrero A, Foster DA
    Novel recruitment of Shc, Grb2, and Sos by fibroblast growth factor receptor-1 in v-Src-transformed cells. Biochemical and biophysical research communications 1998 Feb 13;243(2):555-60
  14. Dell'Era P, Mohammadi M, Presta M
    Different tyrosine autophosphorylation requirements in fibroblast growth factor receptor-1 mediate urokinase-type plasminogen activator induction and mitogenesis. Molecular biology of the cell 1999 Jan;10(1):23-33
  15. Raffioni S, Thomas D, Foehr ED, Thompson LM, Bradshaw RA
    Comparison of the intracellular signaling responses by three chimeric fibroblast growth factor receptors in PC12 cells. Proceedings of the National Academy of Sciences of the United States of America 1999 Jun 22;96(13):7178-83
  16. Sakaguchi K, Lorenzi MV, Matsushita H, Miki T
    Identification of a novel activated form of the keratinocyte growth factor receptor by expression cloning from parathyroid adenoma tissue. Oncogene 1999 Sep 30;18(40):5497-505
  17. Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ
    FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. The EMBO journal 1996 Sep 2;15(17):4629-42
  18. Matsumoto T, Turesson I, Book M, Gerwins P, Claesson-Welsh L
    p38 MAP kinase negatively regulates endothelial cell survival, proliferation, and differentiation in FGF-2-stimulated angiogenesis. The Journal of cell biology 2002 Jan 7;156(1):149-60
  19. Raucci A, Laplantine E, Mansukhani A, Basilico C
    Activation of the ERK1/2 and p38 mitogen-activated protein kinase pathways mediates fibroblast growth factor-induced growth arrest of chondrocytes. The Journal of biological chemistry 2004 Jan 16;279(3):1747-56
  20. Maher P
    p38 mitogen-activated protein kinase activation is required for fibroblast growth factor-2-stimulated cell proliferation but not differentiation. The Journal of biological chemistry 1999 Jun 18;274(25):17491-8
  21. Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I
    Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proceedings of the National Academy of Sciences of the United States of America 2001 May 22;98(11):6074-9
  22. Strutz F, Zeisberg M, Ziyadeh FN, Yang CQ, Kalluri R, Muller GA, Neilson EG
    Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney international 2002 May;61(5):1714-28
  23. Lamothe B, Yamada M, Schaeper U, Birchmeier W, Lax I, Schlessinger J
    The docking protein Gab1 is an essential component of an indirect mechanism for fibroblast growth factor stimulation of the phosphatidylinositol 3-kinase/Akt antiapoptotic pathway. Molecular and cellular biology 2004 Jul;24(13):5657-66
  24. Kim HJ, Kim JH, Bae SC, Choi JY, Kim HJ, Ryoo HM
    The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2. The Journal of biological chemistry 2003 Jan 3;278(1):319-26
  25. Tang CH, Yang RS, Huang TH, Liu SH, Fu WM
    Enhancement of fibronectin fibrillogenesis and bone formation by basic fibroblast growth factor via protein kinase C-dependent pathway in rat osteoblasts. Molecular pharmacology 2004 Sep;66(3):440-9
  26. Haimovitz-Friedman A, Balaban N, McLoughlin M, Ehleiter D, Michaeli J, Vlodavsky I, Fuks Z
    Protein kinase C mediates basic fibroblast growth factor protection of endothelial cells against radiation-induced apoptosis. Cancer research 1994 May 15;54(10):2591-7

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