title: Unconventional EGF-induced ERK1/2-mediated Kv1.3 endocytosis.
abstract: The potassium channel Kv1.3 plays roles in immunity, neuronal development and sensory discrimination. Regulation of Kv1.3 by kinase signaling has been studied. In this context, EGF binds to specific receptors (EGFR) and triggers tyrosine kinase-dependent signaling, which down-regulates Kv1.3 currents. We show that Kv1.3 undergoes EGF-dependent endocytosis. This EGF-mediated mechanism is relevant because is involved in adult neural stem cell fate determination. We demonstrated that changes in Kv1.3 subcellular distribution upon EGFR activation were due to Kv1.3 clathrin-dependent endocytosis, which targets the Kv1.3 channels to the lysosomal degradative pathway. Interestingly, our results further revealed that relevant tyrosines and other interacting motifs, such as PDZ and SH3 domains, were not involved in the EGF-dependent Kv1.3 internalization. However, a new, and yet undescribed mechanism, of ERK1/2-mediated threonine phosphorylation is crucial for the EGF-mediated Kv1.3 endocytosis. Our results demonstrate that EGF triggers the down-regulation of Kv1.3 activity and its expression at the cell surface, which is important for the development and migration of adult neural progenitors.
authors.affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Barcelona, Spain.|Departament de Biologia Celular, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Martínez-Mármol
authors.affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Comes
authors.affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Barcelona, Spain.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Styrczewska
authors.affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Pérez-Verdaguer
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Vicente
authors.affiliation: Departament de Biologia Celular, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Pujadas
authors.affiliation: Departament de Biologia Celular, Universitat de Barcelona, Barcelona, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain.|Vall d´Hebron Institute of Research (VHIR) and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Soriano
authors.affiliation: Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sorkin
authors.affiliation: Molecular Physiology Laboratory, Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina (IBUB), Barcelona, Spain. afelipe@ub.edu.|Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Avda. Diagonal 643, 08028, Barcelona, Spain. afelipe@ub.edu.
authors.forename: Antonio
authors.initials: A
authors.lastname: Felipe
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D002966:Clathrin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D034285:Dynamin II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D020547:Lateral Ventricles / Q000166:cytology / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002070:Butadienes; D002966:Clathrin; D051664:Kv1.3 Potassium Channel; D009570:Nitriles; C113580:U 0126; D004815:Epidermal Growth Factor; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D034285:Dynamin II
keywords: Endocytosis; Map kinases; Olfactory bulb; Sensory neurons; Tyrosine kinases; Voltage-dependent potassium channels