A model for EGFR regulation of AGO2–RAS interaction, and inhibition of PTP1B through AGO2 loss driving OIS. Dotted line separates WT-RAS (left side) and Mutant-RAS (right side) expressing cells. In normal, WT-RAS (blue) expressing cells (steps 1 to 5; left of dotted line): (1) EGFR is activated by EGF ligand binding, (2) pEGFR is endocytosed and interacts with AGO2, (3) phosphorylation of AGO2 leads to a conformational change, leading to (4) displacement of RAS, and (5) increased activation of RAS at the membrane. In mutant RAS (purple) expressing cells (steps 6 to 9; right of dotted line), the loss of AGO2 leads to (6) increased production of ROS and increased MAPK signaling, (7) leading to oxidation and inhibition of PTP1B phosphatase activity, (8) inactivation of PTP1B causes an increase in pEGFR (Y1068), which in turn, (9) feeds forward to cause hyperactive RAS signaling, further MAPK activation, and ultimately resulting in oncogene induced senescence. Created with BioRender.com.