EGFR signaling pathway. Ligand binding induces dimerization and activates the EGFR. Subsequent autophosphorylation of tyrosine residues activates downstream signaling. In the Ras-Raf-MEK-MAPK, one axis of the EGFR signaling cascade, an adaptor protein complex composed of growth factor receptor-bound protein 2 adapter protein (Grb2), which harbors a tyrosine phosphate-docking site, and son of sevenless (SOS), a Ras GDP/GTP exchange factor, then activates the Ras GTPase. After activation, Ras (i.e., KRas) recruits and activates the serine protein Raf (i.e., B-Raf), and subsequent phosphorylation and activation of MEK and then MAPK occurs, resulting in activation of transcription factors in the cell nucleus. The Ras-Raf-MAPK signaling pathway is thought to control cell growth, differentiation, and survival (?apoptosis). The other axis of the EGFR signaling cascade that is important in colorectal carcinogenesis is the PI3K-AKT pathway. Once the EFGR tyrosine residues are phosphorylated, PI3K is translocated to the cell membrane and binds to tyrosine phosphate (through its adaptor subunit p85) which triggers the PI3K catalytic subunit p110 to produce phosphatidylinositol-3,4,5-triphosphate (PIP3). PI3K then promotes AKT activation. Activated AKT (p-AKT), present within the cytoplasm, then activates various targets that result in cell growth, proliferation, and survival (paralleling the Ras-Raf-MEK-MAPK signaling pathway). Importantly, these two axes are closely related and have some overlap. For example, the p110 subunit of PI3K can also be activated via interaction with Ras. Of note, phosphatase with tensin homology (PTEN) is a phosphatase that converts PIP3 back to phosphatidylinositol (4, 5) bisphosphate (PIP2), thereby negatively regulating the PI3K-AKT pathway.
