Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
Metalloprotease
G-alpha
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Transporter
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
DNA
RNA
Compound
Inorganic ion
Predicted metabolite or user's structure
Reaction
Generic receptor
GPCR
Receptors with enzyme activity
Mitochondria
EPR
Golgi
Nucleus
Lysosome
Peroxisome
Cytoplasm
Extracellular

Normal process
Pathological process
Binding
Cleavage
Covalent modifications
Phosphorylation
Dephosphorylation
Transformation
Transport
Catalysis
Transcription regulation
MicroRNA binding
Competition
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Development FGFR signaling pathway


Log In to Post A Comment

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].