Epidermal growth factor (EGF) siganling control various biologic responses such as proliferation, differentiation, cell motility, and survival. EGFR, also known as ErbB1 / HER1, is a member of the ErbB family of receptor tyrosine kinases (RTK). Epidermal growth factor receptor also includes ErbB2 (Neu, HER2), ErbB3 (HER3) and ErbB4 (HER4).
These trans-membrane proteins are activated following binding with ligands such as epidermal growth factor (EGF), transforming growth factor-alpha (TGF-α), epigen, amphiregulin, betacellulin, heparin-binding EGF and epiregulin so as to trigger a reactions path which have several linked elements through the cell from the membrane till the nucleus.
The binding between EGFR and ligand triggers series of downstream intracellular signaling transduction. The RAS-RAF-MEK-MAPK pathway, which controls gene transcription, cell-cycle progression from the G1 phase to the S phase, and cell proliferation, and the PI3K-Akt pathway, which activates a cascade of antiapoptotic and prosurvival signals are the two major well-known intracellular signaling pathways.
Activated EGFR/ErbB recruits various cytoplasmic proteins which transduce and regulate the EGFR function. One of the adaptor proteins, GRB2, binds to the phosphotyrosine residue and recruits SOS to the membrane. SOS activates GDP/GTP exchange which recruits RAF to the membrane. RAF phosphorylates MEKs, which then activates the extracellular signal regulated kinases (ERKs). ERKs activate numbers of transcriptional regulators to induce cell growth and proliferation.
GRB2 or other adaptor proteins recruits PI3Ks, another major mediator of EGFR signaling. PI3Ks convert Phosphatidylinositol-4,5-bisphosphate (PIP2) to Phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 recruits PDK1, and then PDK1 phosphorylates AKT which in turn regulate the activity of various proteins that mediate protein synthesis or apoptosis (Figure 1).
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