RNF144A sustains EGFR signaling to promote EGF-dependent cell proliferation.

RNF144A is a single-pass transmembrane RBR E3 ligase that interacts with and degrades cytoplasmic DNA-PKcs, which is an epidermal growth factor receptor (EGFR)-interacting partner. Interestingly, RNF144A expression is positively correlated with EGFR mRNA and protein levels in several types of cancer. However, the relationship between RNF144A and EGFR is poorly understood. This study reports an unexpected role for RNF144A in the regulation of EGF/EGFR signaling and EGF-dependent cell proliferation. EGFR ligands, but not DNA-damaging agents, induce a DNA-PKcs-independent interaction between RNF144A and EGFR. RNF144A promotes EGFR ubiquitination, maintains EGFR protein, and prolongs EGF/EGFR signaling during EGF stimulation. Moreover, depletion of RNF144A by multiple independent approaches results in a decrease in EGFR expression and EGF/EGFR signaling. RNF144A knockout cells also fail to mount an immediate response to EGF for activation of G/S progression genes. Consequently, depletion of RNF144A reduces EGF-dependent cell proliferation. These defects may be at least in part due to a role for RNF144A in regulating EGFR transport in the intracellular vesicles during EGF treatment.