Figure 1.

EGFR and IGF1R signaling pathways.

Notes: Binding of extracellular ligands results in autophosphorylation of key tyrosine residues in the C-terminal domain of EGFR, which allows downstream proteins to bind through their Src homology 2 (SH2) domains. This elicits the activation of downstream signaling cascades, including Ras/Raf/MEK/ERK, PI3K/Akt, JAK/STAT, and PLC, which ultimately drive tumor-cell proliferation, survival, and invasion. Growth factor-stimulated IGF1R or IR also induces the activation of the Akt- and ERK-signaling pathways. Akt phosphorylates and inactivates TSC2, leading to activation of the mTOR pathway. Activated Akt induces feedback by inhibiting FOXO transcription factors, thereby downregulating the expression of multiple receptor tyrosine kinases (RTKs) such as EGFR, IGF1R, and IR. mTOR-signaling activation exerts negative feedback by inhibiting IRS1, thereby attenuating PI3K/Akt activation from IGF1R or IR. Negative feedback by ERK also occurs through inhibition of Raf activity, and thus self-limits the activation of ERK signaling.