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Development EGFR signaling via PIP3


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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 [1].

Six EGFR ligands have been identified including Epidermal growth factor ( EGF), Amphiregulin, TGF-alpha; Betacellulin, HB-EGF (heparin binding EGF-like growthfactor), and Epiregulin [2]. 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 [1].

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 [3], [4].

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 [5].

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 [6].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 [7].

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 [8].

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 [9].