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The EGFR phosphatase RPTP is a redox-regulated suppressor of promigratory signaling

ABSTRACT: 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 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 RPTPoxidation imaging revealed that phospho-EGFR induces activation of NADPH oxidase, which in turn inhibits RPTPmediated dephosphorylation of EGFR, tilting the autocatalytic RPTP/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/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 results in constitutive promigratory signaling from phosphorylated EGFR monomers. RPTP is thus a suppressor of promigratory oncogenic but not of proliferative EGFR signaling.

SUBMITTER: Dr. Maitreyi, Sadanand Joshi

PROVIDER: S-SCDT-10_15252-EMBJ_2022111806 | biostudies-other |

REPOSITORIES: biostudies-other

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