Both recombinant and endogenous EGFR and FAM83B form a complex. The lysine residue K230 of FAM83B, conserved in other FAM83 family members, including FAM83A and FAM83D, is needed for binding to EGFR and stimulation of EGFR signaling. Through a mechanism that has not been elucidated, FAM83B stimulates basal and EGF-induced EGFR trans-autophosphorylation but dissociates from autophosphorylated EGFR (Cipriano et al. 2014).

FAM83B overexpression stimulates activation of MAPK and mTOR signaling downstream of EGFR, and prolongs activating EGFR, AKT and MAPK phosphorylation, increasing resistance to EGFR-targeting tyrosine kinase inhibitors (TKIs) AG1478, erlotinib, and CL387785 (Cipriano et al. 2012).

FAM83A overexpression similarly increases resistance of EGFR to EGFR-targeting TKIs AG1478, lapatinib, and gefitinib. In EGF-treated cells, tyrosine phosphorylation of FAM83A is increased, plausibly directly by EGFR, but the physical interaction between FAM83A and EGFR has not been reported. Downstream of EGFR activation, FAM83A associates with CRAF and PIK3R1. EGF treatment is not needed for FAM83A to interact with CRAF and PIK3R1 when FAM83A is overexpressed (Lee et al. 2012).

FAM83A-AS1 lncRNA, which is known to increase FAM83A expression, positively regulates EGFR signaling (Zhao et al. 2022).

FAM83D is highly expressed in invasive epithelial ovarian cancer. FAM83D-overexpressing cells demonstrate increased tyrosine phosphorylation of EGFR, as well as increased activating phosphorylation of downstream effectors of EGFR such as CRAF, ERK1/2 (MAPK3/1), and AKT (Zhang et al. 2019), but the direct interaction of FAM83D and EGFR has not been reported.

FAM83A and FAM83D are annotated as candidate binding partners or EGFR.