EGF-dependent re-routing of vesicular recycling switches spontaneous phosphorylation suppression to EGFR signaling

Martin Baumdick, Yannick Brueggemann, Malte Schmick, Georgia Xouri, Ola Sabet, Lloyd Davis, Jason W. Chin, Philippe I. H. Bastiaens*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Autocatalytic activation of epidermal growth factor receptor (EGFR) coupled to dephosphorylating activity of protein tyrosine phosphatases (PTPs) ensures robust yet diverse responses to extracellular stimuli. The inevitable tradeoff of this plasticity is spontaneous receptor activation and spurious signaling. We show that a ligand-mediated switch in EGFR trafficking enables suppression of spontaneous activation while maintaining EGFR's capacity to transduce extracellular signals. Autocatalytic phosphorylation of tyrosine 845 on unliganded EGFR monomers is suppressed by vesicular recycling through perinuclear areas with high PTP1 B activity. Ligandbinding results in phosphorylation of the c-Cbl docking tyrosine and ubiquitination of the receptor. This secondary signal relies on EGF-induced EGFR self-association and switches suppressive recycling to directional trafficking. The re-routing regulates EGFR signaling response by the transit time to late endosomes where it is switched-off by high PTP1 B activity. This ubiquitin-mediated switch in EGFR trafficking is a uniquely suited solution to suppress spontaneous activation while maintaining responsiveness to EGF.

Original languageEnglish
Article number12223
Number of pages28
JournaleLIFE
Volume4
DOIs
Publication statusPublished - 26 Nov 2015

Keywords

  • EPIDERMAL-GROWTH-FACTOR
  • PROTEIN-TYROSINE PHOSPHATASES
  • MEDIATED DOWN-REGULATION
  • FACTOR RECEPTOR
  • PLASMA-MEMBRANE
  • ENDOCYTIC TRAFFICKING
  • ACTIVATION
  • CELLS
  • KINASE
  • CBL

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