eIF4E S209 phosphorylation licenses myc- and stress-driven oncogenesis

Mutational activation of Wnt/Myc and RAS signaling promotes colorectal cancer (CRC) development and deregulates translation. Phosphorylation of the cap binding protein eIF4E (Serine 209) is commonly elevated in cancer such as CRC yet dispensable for normal development. To better understand an oncogenic role of eIF4ES209, we generated eIF4E (S209A/+) heterozygous knockin (4EKI) HCT 116 human colorectal cancer (CRC) cells. 4EKI had little or no effect on total eIF4E levels, cap binding or global translation, while markedly reduced HCT 116 cell growth in spheroids and mice. 4EKI strongly inhibited Myc and ATF4 translation, the integrated Stress Response (ISR)-dependent glutamine metabolic signature, AKT activation and proliferation in vivo. p-eIF4E was found to be highly elevated in CRC precursor lesions in mouse and human. 4EKI inhibited polyposis in APC+/min mice by suppressing Myc protein and AKT activation. Furthermore, mutant KRAS cooperated with p-eIF4E and Myc to promote ISR-depende...