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 RPTP gamma 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-EGFR(2) dimers. Single cell RPTP gamma oxidation imaging revealed that phospho-EGFR induces activation of NADPH oxidase, which in turn inhibits RPTP gamma-mediated dephosphorylation of EGFR, tilting the autocatalytic RPTP gamma/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 RPTP gamma/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 RPTP gamma results in constitutive promigratory signaling from phosphorylated EGFR monomers. RPTP gamma is thus a suppressor of promigratory oncogenic but not of proliferative EGFR signaling.