Prolonged EGFR signaling by ERBB2-mediated sequestration at the plasma membrane.
We have analyzed the spatial-temporal regulation of epidermal growth factor receptor (EGFR) phosphorylation by the orphan erbB2 receptor. It is shown that EGFR association with erbB2 is sufficient to prolong and enhance the net phosphorylation of EGFR, independent of the kinase activity of erbB2. This enhanced EGFR signaling was rather caused by erbB2-mediated retention of phosphorylated EGFR at the plasma membrane (PM), thereby preventing EGFR dephosphorylation and signal termination by endomembrane-bound protein tyrosine phosphatases (PTPs). EGF-induced EGFR internalization was indeed blocked in the presence of high levels of erbB2 or if cbl binding of EGFR was impaired. This erbB2-mediated blockage of the entry of activated EGFR into clathrin-coated vesicles could be alleviated by antibody-mediated disruption of the interaction between EGFR and erbB2. These results identify erbB2-mediated dominant trapping of phosphorylated EGFR at the PM as a mechanism that prolongs EGFR signaling, by sequestration of activated EGFR away from intracellular sites of high PTP activity.
Offterdinger
Martin
M
Division of Cell Biology, Biocenter, Innsbruck Medical University, Fritz-Pregl-Str. 3, A-6020 Innsbruck, Austria. martin.offterdinger@i-med.ac.at
Bastiaens
Philippe I
PI
D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004705:Endocytosis / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D014162:Transfection
D066246:ErbB Receptors; D049452:Green Fluorescent Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases