Affiliation:
1. Department of Systemic Cell Biology Max Planck Institute for Molecular Physiology Dortmund Germany
2. Faculty of Chemistry and Chemical Biology TU Dortmund Dortmund Germany
Abstract
AbstractSpatially 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.
Funder
H2020 European Research Council
Publisher
Springer Science and Business Media LLC
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience
Cited by
2 articles.
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