RPTPγ is a redox-regulated suppressor of promigratory EGFR signaling

Abstract

AbstractSpatially-organized interaction dynamics between proto-oncogenic epidermal growth factor receptor (EGFR) and protein tyrosine phosphatases (PTPs) determine EGFR’s phosphorylation response to growth factors and thereby cellular behavior within developing tissues. We show here, that and how the coupling between EGFR and RPTPγ activity leads to migratory signaling responses to very low, physiological growth factor stimuli while suppressing aberrant, spontaneous signaling. Single cell imaging of EGFR phosphorylation and PTP oxidation revealed that RPTPγ fully suppresses spontaneous EGFR phosphorylation, while EGF-induced NADPH-oxidase activity enables promigratory signaling responses at the plasma membrane by H2O2-mediated oxidative inhibition of RPTPγ’s phosphatase activity. The EGF-dependent toggle switch dynamics between interacting EGFR monomers and RPTPγ thereby enables autocatalytically amplified phosphorylation responses to very low, physiological, EGF levels even at sparse receptor expression. This signaling mechanism is distinct from the proliferative signaling stemming from liganded endosomal EGFR complexes at high growth factor concentrations. Accordingly, RPTPγ knock-out results in spontaneous promigratory EGFR signaling but loss of proliferative signaling. We thereby provide evidence of RPTPγ’s suppressor function of oncogenic, promigratory EGFR-signaling from the plasma membrane.