The EGFR phosphatase RPTPγ is a redox‐regulated suppressor of promigratory signaling.

Spatially organized reaction dynamics between proto‐oncogenic epidermal growth factor receptor (EGFR) and protein tyrosine phosphatases determine EGFR phosphorylation dynamics in response to growth factors and thereby cellular behavior within developing tissues. We show that the reaction dynamics of mutual inhibition between RPTPγ phosphatase and autocatalytic ligandless EGFR phosphorylation enable highly sensitive promigratory EGFR signaling responses to subnanomolar EGF levels, when < 5% receptors are occupied by EGF. EGF thereby triggers an autocatalytic phospho‐EGFR reaction by the initial production of small amounts of phospho‐EGFR through transient, asymmetric EGF‐EGFR2 dimers. Single cell RPTPγ oxidation imaging revealed that phospho‐EGFR induces activation of NADPH oxidase, which in turn inhibits RPTPγ‐mediated dephosphorylation of EGFR, tilting the autocatalytic RPTPγ/EGFR toggle switch reaction towards ligandless phosphorylated EGFR. Reversibility of this reaction to EGF is maintained by the constitutive phosphatase activity of endoplasmic reticulum‐associated TCPTP. This RPTPγ/EGFR reaction at the plasma membrane causes promigratory signaling that is separated from proliferative signaling induced by accumulated, liganded, phosphorylated EGF‐EGFR in endosomes. Accordingly, loss of RPTPγ results in constitutive promigratory signaling from phosphorylated EGFR monomers. RPTPγ is thus a suppressor of promigratory oncogenic but not of proliferative EGFR signaling. Synopsis: Inhibition of RPTPγ‐catalyzed EGFR dephosphorylation is mediated by NADPH oxidase, and required for the phosphorylation of EGFR in response to growth factors. Here, the ROS‐mediated toggle‐switch coupling of RPTPγ to autocatalytic ligandless EGFR phosphorylation is shown to enable ultrasensitive EGFR activation and a promigratory response at the plasma membrane to physiological levels of EGF.EGF triggers an autocatalytic phosphorylation of ligandless EGFR by catalytic generation of small amounts of phospho‐EGFR through transient, asymmetric EGF‐EGFR2 dimers.The EGFR/RPTPγ (auto‐)catalytic toggle‐switch reaction is distinct from the canonical EGFR phosphorylation that occurs within stable EGF2‐EGFR2 dimers.RPTPγ/EGFR reaction dynamics are poised at the edge of bistability by endoplasmic reticulum‐associated TCPTP phosphatase activity, thus enabling cells to reversibly respond to low EGF stimuli while being robust to noise.RPTPγ is a suppressor of promigratory signaling from ligandless EGFR at the plasma membrane but not of proliferative signaling of liganded EGFR from endosomes. [ABSTRACT FROM AUTHOR]