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
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,
(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
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
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