title: Ubiquitination switches EphA2 vesicular traffic from a continuous safeguard to a finite signalling mode.
abstract: Autocatalytic phosphorylation of receptor tyrosine kinases (RTKs) enables diverse, context-dependent responses to extracellular signals but comes at the price of autonomous, ligand-independent activation. Using a conformational biosensor that reports on the kinase activity of the cell guidance ephrin receptor type-A (EphA2) in living cells, we observe that autonomous EphA2 activation is suppressed by vesicular recycling and dephosphorylation by protein tyrosine phosphatases 1B (PTP1B) near the pericentriolar recycling endosome. This spatial segregation of catalytically superior PTPs from RTKs at the plasma membrane is essential to preserve ligand responsiveness. Ligand-induced clustering, on the other hand, promotes phosphorylation of a c-Cbl docking site and ubiquitination of the receptor, thereby redirecting it to the late endosome/lysosome. We show that this switch from cyclic to unidirectional receptor trafficking converts a continuous suppressive safeguard mechanism into a transient ligand-responsive signalling mode.
authors: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
authors: Ola
authors: O
authors: Sabet
authors: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
authors: Rabea
authors: R
authors: Stockert
authors: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
authors: Georgia
authors: G
authors: Xouri
authors: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.|Faculty of Chemistry and Chemical Biology, TU Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany.
authors: Yannick
authors: Y
authors: Brüggemann
authors: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
authors: Angel
authors: A
authors: Stanoev
authors: Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.|Faculty of Chemistry and Chemical Biology, TU Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany.
authors: Philippe I H
authors: PIH
authors: Bastiaens
mesh_terms: D000818:Animals; D015374:Biosensing Techniques; D002460:Cell Line; D005453:Fluorescence; D006801:Humans; D016254:Mutagenesis, Insertional; D011487:Protein Conformation; D021381:Protein Transport / Q000502:physiology*; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D036104:Receptor, EphA2