Development EGFR signaling via PIP3
EGFR signaling via PIP3 The Epidermal growth factor receptor ( EGFR ) belongs to the ERBB family ofreceptor tyrosine kinases, which consists of four closely related members: EGFRand v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derivedoncogene homolog ( ERBB2 ), ERBB3 and ERBB4. These receptors couple binding ofextracellular growth factor ligands to intracellular signaling pathways and regulatediverse biologic responses, including proliferation, differentiation, cell motility, andsurvival . Six EGFR ligands have been identified including Epidermal growth factor ( EGF), Amphiregulin, TGF-alpha; Betacellulin, HB-EGF (heparin binding EGF-like growthfactor), and Epiregulin . ERBB2 is a unique member of the ErbBfamily as it does not bind any of the known ligands with high affinity, but it is thepreferred heterodimeric partner for other EGFRs . Ligand-induced receptor dimerization and subsequent autophosphorylation of distincttyrosine residues creates docking sites for various membrane-targeted proteins, includingadaptor proteins Growth factor receptor-bound protein 2 ( Grb2 ), Cas-Br-M(murine) ecotropic retroviral transforming sequence ( c-Cbl ), GRB2-associatedbinding protein 1 ( GAB1 ), Insulin receptor substrates 1 and 2 ( IRS-1 andIRS-2), GRB7, and DOK2. One signaling cascade stimulated by EGF is the Phosphatidylinositol 3-kinase (PI3K ) - pathway. EGFR can recruit Phosphoinositide-3-kinase, regulatorysubunit ( PI3K reg class IA ) via set of adaptor protein, such as c-Cbl,GAB1, IRS-1 and IRS-2 , . c-Cbl is a target of tyrosine phosphorylation upon stimulation through theEGFR tyrosine kinase activity. c-Cbl can also form protein-proteininteractions with through its proline-rich regions with SH3 domain of adaptor proteinssuch as Grb2, which also is recruited by EGFR . The activated Phosphoinositide-3-kinase, catalytic ( PI3K cat class IA )converts phosphatidylinositol 4,5-biphosphate ( PtdIns(4,5)P2 ) tophosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ), which is a secondarymessenger involved in the regulation of various process .PtdIns(3,4,5)P3 associates with the inner lipid bilayer of the plasma membrane topromote the recruitment of proteins with pleckstrin homology (PH) domains. One of them isv-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ), which is a crucialmediator of various cell process, such as apoptosis, cell cycle, protein synthesis,regulation of metabolism . Adaptor proteins such as GAB1, IRS-1, IRS-2 also havepleckstrin homology domains and are recruited by PtdIns(3,4,5)P3 to the membranecreating a positive feedback regulatory loop . Another protein with a pleckstrin homology domain is Vav 2 guanine nucleotide exchangefactor ( VAV-2 ), which activates the Rho family of Ras-related GTPases, such asRas-related C3 botulinum toxin substrate 1 ( Rac1 ). Activated EGFRphosphorylates VAV-2, but this does not correlate with tyrosine phosphorylation ofVAV-2. EGF regulates the VAV-2 activity basically throughPI3K activation, whereas tyrosine phosphorylation of VAV-2 is required formediating protein-protein interactions .