CD317 Activates EGFR by Regulating Its Association with Lipid Rafts

EGFR regulates various fundamental cellular processes, and its constitutive activation is a common driver for cancer. Anti-EGFR therapies have shown benefit in cancer patients, yet drug resistance almost inevitably develops, emphasizing the need for a better understanding of the mechanisms that govern EGFR activation. Here we report that CD317, a surface molecule with a unique topology, activated EGFR in hepatocellular carcinoma (HCC) cells by regulating its localization on the plasma membrane. CD317 was upregulated in HCC cells, promoting cell-cycle progression and enhancing tumorigenic potential in a manner dependent on EGFR. Mechanistically, CD317 associated with lipid rafts and released EGFR from these ordered membrane domains, facilitating the activation of EGFR and the initiation of downstream signaling pathways, including the Ras–Raf–MEK–ERK and JAK–STAT pathways. Moreover, in HCC mouse models and patient samples, upregulation of CD317 correlated with EGFR activation. These results reveal a previously unrecognized mode of regulation for EGFR and suggest CD317 as an alternative target for treating EGFR-driven malignancies. Significance: Activation of EGFR by CD317 in hepatocellular carcinoma cells suggests CD317 as an alternative target for treating EGFR-dependent tumors.