PI3K cat class IA, MKK4/7, RAC1, GRB2, 18.104.22.168, PIP2, AKT(PKB), VAV-2, PI3K reg class IA, IRS-2, IRS-1, PIP3, 22.214.171.124, PTEN, GAB1, JNK(MAPK8-10), ERBB2, EGFR, MLK2(MAP3K10), EGF, c-Cbl, PDK (PDPK1)
EGFR signaling via PIP3
The Epidermal growth factor receptor ( EGFR ) belongs to the ERBB family of receptor tyrosine kinases, which consists of four closely related members: EGFR and v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog ( ERBB2 ), ERBB3 and ERBB4. These receptors couple binding of extracellular growth factor ligands to intracellular signaling pathways and regulate diverse biologic responses, including proliferation, differentiation, cell motility, and survival .
Six EGFR ligands have been identified including Epidermal growth factor ( EGF ), Amphiregulin, TGF-alpha; Betacellulin, HB-EGF (heparin binding EGF-like growth factor), and Epiregulin . ERBB2 is a unique member of the ErbB family as it does not bind any of the known ligands with high affinity, but it is the preferred heterodimeric partner for other EGFRs .
Ligand-induced receptor dimerization and subsequent autophosphorylation of distinct tyrosine residues creates docking sites for various membrane-targeted proteins, including adaptor proteins Growth factor receptor-bound protein 2 ( Grb2 ), Cas-Br-M (murine) ecotropic retroviral transforming sequence ( c-Cbl ), GRB2-associated binding protein 1 ( GAB1 ), Insulin receptor substrates 1 and 2 ( IRS-1 and IRS-2), GRB7, and DOK2.
One signaling cascade stimulated by EGF is the Phosphatidylinositol 3-kinase ( PI3K ) - pathway. EGFR can recruit Phosphoinositide-3-kinase, regulatory subunit ( 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 the EGFR tyrosine kinase activity. c-Cbl can also form protein-protein interactions with through its proline-rich regions with SH3 domain of adaptor proteins such 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 ) to phosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ), which is a secondary messenger involved in the regulation of various process . PtdIns(3,4,5)P3 associates with the inner lipid bilayer of the plasma membrane to promote the recruitment of proteins with pleckstrin homology (PH) domains. One of them is v-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ), which is a crucial mediator of various cell process, such as apoptosis, cell cycle, protein synthesis, regulation of metabolism .
Adaptor proteins such as GAB1, IRS-1, IRS-2 also have pleckstrin homology domains and are recruited by PtdIns(3,4,5)P3 to the membrane creating a positive feedback regulatory loop .
Another protein with a pleckstrin homology domain is Vav 2 guanine nucleotide exchange factor ( VAV-2 ), which activates the Rho family of Ras-related GTPases, such as Ras-related C3 botulinum toxin substrate 1 ( Rac1 ). Activated EGFR phosphorylates VAV-2, but this does not correlate with tyrosine phosphorylation of VAV-2. EGF regulates the VAV-2 activity basically through PI3K activation, whereas tyrosine phosphorylation of VAV-2 is required for mediating protein-protein interactions .