Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin

Significance Epidermal growth factor receptor (EGFR) signal transduction plays a major role in growth, proliferation, and differentiation of mammalian cells. Although inactive rhomboids (iRhoms) are cardinal regulators of EGFR signaling in Drosophila melanogaster , their physiological role in regulating EGFR signaling and their substrates in mammals remain unclear. Here, we show that iRhoms are short-lived proteins, but dominant mutations increase their protein stability and stimulate secretion of specific EGF family ligand amphiregulin independent of metalloprotease activity. This study demonstrates the significance of mammalian iRhoms in regulating an EGFR signaling event that promotes accelerated wound healing and triggers tumorigenesis. Given their ability to regulate EGFR signaling in parallel with metalloproteases, iRhoms can be potential therapeutic targets in impaired wound healing and cancer.