Development - FGFR signaling pathway

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FGFR signaling pathway

Fibroblast growth factor 2 (FGF2) has been implicated in diverse cellular processes, including apoptosis, cell survival, chemotaxis, cell adhesion, migration, differentiation, and proliferation [1].

FGF2 induces biological responses by binding to and activating Fibroblast growth factor receptor 1 (FGFR1), a subfamily of cell surface receptor tyrosine kinases (RTKs). FGFR1 interacts with components of the extracellular matrix, in particular heparan sulfate proteoglycans (such as Perlecan). Perlecan protects the FGF2 from thermal denaturation and proteolysis, and is required for activation of the FGFR1 and for defining the mode of interaction between specific FGF-FGFR pairs. Heparin binds directly to FGF2 and FGFR1 and thereby modulates activation of the FGFR1 [2].

Transmembrane heparan sulfate proteoglycans (Syndecan-1, Syndecan-2 and Syndecan-4) are able to bind FGF2 to heparan sulfate chains and present it to the FGFR1. Remodeling of heparan sulfate chains may affect FGF2 signaling [3], [4].

The most common pathway employed by FGF2 is the mitogen-activated protein kinase (MAPK) pathway. The process involves the lipid-anchored docking protein Fibroblast growth factor receptor substrate 2 (FRS2) that constitutively binds FGFR1 even when the receptor is not activated. FGFR1 can phosphorylate FRS2 and Src homology 2 domain containing transforming protein (Shc). Phosphorylated FRS2 binds the adapter protein Growth factor receptor bound 2 (GRB2) and the Protein tyrosine phosphatase, non-receptor type 11 (SHP-2). In FGFR1/ FRS2 signaling pathway, SHP-2 acts as adapter protein. Shc and GRB2 form a complex with the Guanine nucleotide exchange factor Son of sevenless proteins (SOS). Translocation of this complex to the plasma membrane by binding to phosphorylated FRS2 allows SOS to activate v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) by GTP exchange due to its close proximity to membrane-bound H-Ras. Once in the active GTP-bound state, H-Ras interacts with several effector proteins, including v-Raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1). That results in activation of the Mitogen-activated protein kinase kinases 1 and 2 (MEK1/2)/ Mitogen-activated protein kinases 1 and 3 (ERK1/2) signaling cascade. This cascade leads to phosphorylation of the target transcription factor ELK1 [5], [6], [7], [8].

GRB2 is bound to tyrosine-phosphorylated FRS2, and the C-terminal SH3 domain of GRB2 forms a complex with the proline-rich region of GRB2-associated binding protein 1 (GAB1) to serve as an interface between these two docking proteins. Phosphatidylinositol-3-kinase kinase (PI3K) is one of the effectors of GAB1 and thus might be involved in FGF-induced activation of PI3K [9].

Assembly of FRS2/ GRB2/ GAB1 complex induced by FGF stimulation leads to activation of the PI3K and the downstream effector proteins such as the v-AKT murine thymoma viral oncogene homolog (AKT) which cellular localization and activity is regulated by product of PI3K, Phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) [10].

Cas-Br-M ecotropic retroviral transforming sequence (c-Cbl) is a regulator that functions as the ubiquitin ligase. It ubiquitinates and promotes the degradation of a variety of cell signaling proteins. c-Cbl is recruited by GRB2 to the FRS2 multiprotein complex in response to the FGF2 stimulation, resulting in ubiquitination of FRS2 and FGFR1 [11].

FGF2 activates stress-activated protein kinase/c-Jun N-terminal kinase (JNK(MAPK8-10)) and the transcription factor c-Jun. The adaptor protein CRK is tyrosine-phosphorylated by FGFR1. Formation of this stable complex between the CRK and FGFR1 is dependent on phosphorylated state of the receptor. Interaction between CRK and guanine nucleotide exchange factor DOCK1 induces the Ras-related C3 botulinum toxin substrate 1 (Rac1) activation and its translocation to the membrane. Activated Rac1 stimulates the cascade that involves p21-Activated kinase 1 (PAK1)/ Mitogen-activated protein kinase kinase kinase 1 (MEKK1)/ Dual specificity Mitogen-activated protein kinase kinase 4 (MEK4)/ JNK(MAPK8-10) by a Ras-independent mechanism [12].

FGF2 mediates activation of p38 MAPK via adaptor proteins Src homology 2 domain containing adaptor protein B (SHB), Epidermal growth factor receptor pathway substrate 8 (EPS8) and Abl-interactor 1 (E3b1(ABI-1)). EPS8 and E3b1(ABI-1) participate in the transduction of signals to Rac1, by regulating Rac-specific activities of the guanine nucleotide exchange factors (GEF). EPS8, E3b1(ABI-1) and SOS form a trimeric complex that exhibits Rac-specific GEF activity. Rac1 activates Mitogen-activated protein kinase kinase kinase 11 (MLK3(MAP3K11)), Mitogen-activated protein kinase kinase 6 (MEK6(MAP2K6)), and p38 MAPK and its downstream target MAPK-activated protein kinase-2 (MAPKAPK-2). That ultimately leads to transcriptional activation of the cyclic AMP response element-binding protein (CREB1) and activation of the transcription factor ATF-2 [13], [14].

FGF2 plays a critical role in the hydrolysis of membrane phospholipids in cells. Upon binding to FGFR1, FGF2 stimulates cytosolic form of Phospholipase C-gamma1 (PLC-gamma 1) that in turn hydrolyzes Phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) to Diacylglycerol (DAG) and Inositol trisphosphate (IP3). DAG and IP3 are second messengers. IP3 activates IP3 receptor and induces the release of Ca('2+) from intracellular Ca('2+) storage and accumulation of Ca('2+) in the cytoplasm. DAG activates Protein kinase C delta (PKC-delta) [15].

Fibroblast growth factor 2 (FGF2) is a known inducer of epithelial-to-mesenchymal transition (EMT). FGF2 induces EMT via PI3K [16], [17], [18].

References:

  1. Bottcher RT, Niehrs C
    Fibroblast growth factor signaling during early vertebrate development. Endocrine reviews 2005 Feb;26(1):63-77
  2. 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
  3. Steinfeld R, Van Den Berghe H, David G
    Stimulation of fibroblast growth factor receptor-1 occupancy and signaling by cell surface-associated syndecans and glypican. The Journal of cell biology 1996 Apr;133(2):405-16
  4. Tkachenko E, Rhodes JM, Simons M
    Syndecans: new kids on the signaling block. Circulation research 2005 Mar 18;96(5):488-500
  5. Suyama K, Shapiro I, Guttman M, Hazan RB
    A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer cell 2002 Oct;2(4):301-14
  6. Ishibe T, Nakayama T, Okamoto T, Aoyama T, Nishijo K, Shibata KR, Shima Y, Nagayama S, Katagiri T, Nakamura Y, Nakamura T, Toguchida J
    Disruption of fibroblast growth factor signal pathway inhibits the growth of synovial sarcomas: potential application of signal inhibitors to molecular target therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 2005 Apr 1;11(7):2702-12
  7. Katoh M, Katoh M
    FGF signaling network in the gastrointestinal tract (review). International journal of oncology 2006 Jul;29(1):163-8
  8. Yang H, Xia Y, Lu SQ, Soong TW, Feng ZW
    Basic fibroblast growth factor-induced neuronal differentiation of mouse bone marrow stromal cells requires FGFR-1, MAPK/ERK, and transcription factor AP-1. The Journal of biological chemistry 2008 Feb 29;283(9):5287-95
  9. Hadari YR, Gotoh N, Kouhara H, Lax I, Schlessinger J
    Critical role for the docking-protein FRS2 alpha in FGF receptor-mediated signal transduction pathways. Proceedings of the National Academy of Sciences of the United States of America 2001 Jul 17;98(15):8578-83
  10. 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
  11. Wong A, Lamothe B, Lee A, Schlessinger J, Lax I
    FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl. Proceedings of the National Academy of Sciences of the United States of America 2002 May 14;99(10):6684-9
  12. Larsson H, Klint P, Landgren E, Claesson-Welsh L
    Fibroblast growth factor receptor-1-mediated endothelial cell proliferation is dependent on the Src homology (SH) 2/SH3 domain-containing adaptor protein Crk. The Journal of biological chemistry 1999 Sep 3;274(36):25726-34
  13. 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
  14. 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
  15. 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
  16. Lee HT, Kay EP
    FGF-2 induced reorganization and disruption of actin cytoskeleton through PI 3-kinase, Rho, and Cdc42 in corneal endothelial cells. Molecular vision 2003 Dec 8;9:624-34
  17. Ko MK, Kay EP
    Regulatory role of FGF-2 on type I collagen expression during endothelial mesenchymal transformation. Investigative ophthalmology & visual science 2005 Dec;46(12):4495-503
  18. Lee JG, Kay EP
    Cross-talk among Rho GTPases acting downstream of PI 3-kinase induces mesenchymal transformation of corneal endothelial cells mediated by FGF-2. Investigative ophthalmology & visual science 2006 Jun;47(6):2358-68

  1. Bottcher RT, Niehrs C
    Fibroblast growth factor signaling during early vertebrate development. Endocrine reviews 2005 Feb;26(1):63-77
  2. 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
  3. Steinfeld R, Van Den Berghe H, David G
    Stimulation of fibroblast growth factor receptor-1 occupancy and signaling by cell surface-associated syndecans and glypican. The Journal of cell biology 1996 Apr;133(2):405-16
  4. Tkachenko E, Rhodes JM, Simons M
    Syndecans: new kids on the signaling block. Circulation research 2005 Mar 18;96(5):488-500
  5. Suyama K, Shapiro I, Guttman M, Hazan RB
    A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer cell 2002 Oct;2(4):301-14
  6. Ishibe T, Nakayama T, Okamoto T, Aoyama T, Nishijo K, Shibata KR, Shima Y, Nagayama S, Katagiri T, Nakamura Y, Nakamura T, Toguchida J
    Disruption of fibroblast growth factor signal pathway inhibits the growth of synovial sarcomas: potential application of signal inhibitors to molecular target therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 2005 Apr 1;11(7):2702-12
  7. Katoh M, Katoh M
    FGF signaling network in the gastrointestinal tract (review). International journal of oncology 2006 Jul;29(1):163-8
  8. Yang H, Xia Y, Lu SQ, Soong TW, Feng ZW
    Basic fibroblast growth factor-induced neuronal differentiation of mouse bone marrow stromal cells requires FGFR-1, MAPK/ERK, and transcription factor AP-1. The Journal of biological chemistry 2008 Feb 29;283(9):5287-95
  9. Hadari YR, Gotoh N, Kouhara H, Lax I, Schlessinger J
    Critical role for the docking-protein FRS2 alpha in FGF receptor-mediated signal transduction pathways. Proceedings of the National Academy of Sciences of the United States of America 2001 Jul 17;98(15):8578-83
  10. 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
  11. Wong A, Lamothe B, Lee A, Schlessinger J, Lax I
    FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl. Proceedings of the National Academy of Sciences of the United States of America 2002 May 14;99(10):6684-9
  12. Larsson H, Klint P, Landgren E, Claesson-Welsh L
    Fibroblast growth factor receptor-1-mediated endothelial cell proliferation is dependent on the Src homology (SH) 2/SH3 domain-containing adaptor protein Crk. The Journal of biological chemistry 1999 Sep 3;274(36):25726-34
  13. 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
  14. 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
  15. 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
  16. Lee HT, Kay EP
    FGF-2 induced reorganization and disruption of actin cytoskeleton through PI 3-kinase, Rho, and Cdc42 in corneal endothelial cells. Molecular vision 2003 Dec 8;9:624-34
  17. Ko MK, Kay EP
    Regulatory role of FGF-2 on type I collagen expression during endothelial mesenchymal transformation. Investigative ophthalmology & visual science 2005 Dec;46(12):4495-503
  18. Lee JG, Kay EP
    Cross-talk among Rho GTPases acting downstream of PI 3-kinase induces mesenchymal transformation of corneal endothelial cells mediated by FGF-2. Investigative ophthalmology & visual science 2006 Jun;47(6):2358-68

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