title: EGF-dependent re-routing of vesicular recycling switches spontaneous phosphorylation suppression to EGFR signaling.
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 PTP1B activity. Ligand-binding 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 PTP1B activity. This ubiquitin-mediated switch in EGFR trafficking is a uniquely suited solution to suppress spontaneous activation while maintaining responsiveness to EGF.
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Baumdick
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.|Faculty of Chemistry and Chemical Biology, Technical University of Dortmund, Dortmund, Germany.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Brüggemann
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Schmick
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
authors.forename: Georgia
authors.initials: G
authors.lastname: Xouri
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
authors.forename: Ola
authors.initials: O
authors.lastname: Sabet
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Davis
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Chin
authors.affiliation: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.|Faculty of Chemistry and Chemical Biology, Technical University of Dortmund, Dortmund, Germany.
authors.forename: Philippe I H
authors.initials: PI
authors.lastname: Bastiaens
mesh_terms: D000818:Animals; D002460:Cell Line; D022162:Cytoplasmic Vesicles / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: autocatalysis; cell biology; computational biology; none; partitioned phosphatase activities; recycling endosome; spontaneous phosphorylation; systems biology; ubiquitination; vesicular EGFR trafficking