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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