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Development FGFR signaling pathway

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Development FGFR signaling pathway

FGFR signaling pathway

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

FGF-2 induces biological responses by binding to and activating Fibroblastgrowth factor receptor 1 ( FGFR1 ), a subfamily of cell surface receptor tyrosinekinases (RTKs). FGFR1 interacts with components of the extracellular matrix, inparticular heparan sulfate proteoglycans (such as Perlecan ). Perlecanprotects the FGF-2 from thermal denaturation and proteolysis, and is required foractivation of the FGFR1 and for defining the mode of interaction between specificFGF-FGFR pairs. Heparin binds directly to FGF-2 and FGFR1 andthereby modulates activation of the FGFR1 [2].

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

The most common pathway employed by FGF-2 is the mitogen-activated proteinkinase (MAPK) pathway. The process involves the lipid-anchored docking protein Fibroblastgrowth factor receptor substrate 2 ( FRS2 ) that constitutively binds FGFR1even when the receptor is not activated. FGFR1 can phosphorylate FRS2 andSrc 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 Sonof sevenless proteins ( SOS ). Translocation of this complex to the plasmamembrane by binding to phosphorylated FRS2 allows SOS to activate v-Ha-rasHarvey rat sarcoma viral oncogene homolog ( H-Ras ) by GTP exchange due to itsclose 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 leukemiaviral oncogene homolog 1 ( c-Raf-1 ). That results in activation of theMitogen-activated protein kinase kinases 1 and 2 ( MEK1/2 )/ Mitogen-activatedprotein kinases 1 and 3 ( ERK1/2 ) signaling cascade. This cascade leads tophosphorylation of the target transcription factor ELK1 [5], [6], [7], [8].

GRB2 is bound to tyrosine-phosphorylated FRS2, and the C-terminal SH3domain of GRB2 forms a complex with the proline-rich region of GRB2-associatedbinding protein 1 ( GAB1 ) to serve as an interface between these two dockingproteins. Phosphatidylinositol-3-kinase kinase ( PI3K ) is one of the effectors ofGAB1 and thus might be involved in FGF-induced activation of PI3K [9].

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

Cas-Br-M ecotropic retroviral transforming sequence ( c-Cbl ) is a regulatorthat functions as the ubiquitin ligase. It ubiquitinates and promotes the degradation ofa variety of cell signaling proteins. c-Cbl is recruited by GRB2 to theFRS2 multiprotein complex in response to the FGF-2 stimulation, resultingin ubiquitination of FRS2 and FGFR1 [11].

FGF-2 activates stress-activated protein kinase/c-Jun N-terminal kinase (JNK(MAPK8-10) ) and the transcription factor c-Jun. The adaptor proteinCRK is tyrosine-phosphorylated by FGFR1. Formation of this stable complexbetween the CRK and FGFR1 is dependent on phosphorylated state of thereceptor. Interaction between CRK and guanine nucleotide exchange factorDOCK1 induces the Ras-related C3 botulinum toxin substrate 1 ( Rac1 )activation and its translocation to the membrane . Activated Rac1stimulates the cascade that involves p21-Activated kinase 1 ( PAK1 )/Mitogen-activated protein kinase kinase kinase 1 ( MEKK1 )/ Dual specificitymitogen-activated protein kinase kinase 4 ( MEK4 )/c-Jun N-terminal kinase (JNK(MAPK8-10) ) by a Ras-independent mechanism [12].

FGF-2 mediates activation of p38 MAPK via adaptor proteins Src homology2 domain containing adaptor protein B ( SHB ), Epidermal growth factor receptorpathway substrate 8 ( EPS8 ) and Abl-interactor 1 ( E3b1(ABI-1) ).EPS8 and E3b1(ABI-1) participate in the transduction of signals toRac1, by regulating Rac-specific activities of the guanine nucleotide exchangefactors (GEF). EPS8, E3b1(ABI-1) and SOS form a trimeric complexthat exhibits Rac-specific GEF activity. Rac1 activates Mitogen-activated proteinkinase kinase kinase 11 ( MLK3(MAP3K11) ), Mitogen-activated protein kinase kinase6 ( MEK6(MAP2K6) ), and p38 MAPK and its downstream target MAPK-activatedprotein kinase-2 ( MAPKAPK-2 ). That ultimately leads to transcriptionalactivation of the cyclic AMP response element-binding protein ( CREB1 ) andactivation of the transcription factor ATF-2 [13], [14].

FGF-2 plays a critical role in the hydrolysis of membrane phospholipids incells. Upon binding to FGFR1, FGF-2 stimulates cytosolic form ofPhospholipase C-gamma1 ( PLC-gamma 1 ) that in turn hydrolyzesPhosphatidylinositol 4,5 bisphosphate ( PI(4,5)P2 ) to Diacylglycerol ( DAG) and Inositol trisphosphate ( IP3 ). DAG and IP3 are secondmessengers. IP3 activates IP3 receptor and induces the release ofCa(2+) from intracellular Ca(2+) storage and accumulation of Ca(2+)in the cytoplasm. DAG activates Protein kinase C delta ( PKC delta ) [15].