FAM83B mediates EGFR- and RAS-driven oncogenic transformation

Aberrant regulation of growth signaling is a hallmark of cancer development that often occurs through the constitutive activation of growth factor receptors or their downstream effectors. Using validation-based insertionalmutagenesis (VBIM), we identified family with sequence similarity 83, member B (FAM83B), basedon its ability to substitute for RAS in the transformation of immortalized human mammary epithelial cells(HMECs). We found that FAM83B coprecipitated with a downstream effector of RAS, CRAF. Binding ofFAM83B with CRAF disrupted CRAF/14-3-3 interactions and increased CRAF membrane localization, resultingin elevated MAPK and mammalian target of rapamycin (mTOR) signaling. Ablation of FAM83B inhibitedthe proliferation and malignant phenotype of tumor-derived cells or RAS-transformed HMECs, implicatingFAM83B as a key intermediary in EGFR/RAS/MAPK signaling. Analysis of human tumor specimens revealedthat FAM83B expression was significantly elevated in cancer and was associated with specific cancer subtypes,increased tumor grade, and decreased overall survival. Cumulatively, these results suggest that FAM83B is anoncogene and potentially represents a new target for therapeutic intervention.