title: Differential roles of Grb2 and AP-2 in p38 MAPK- and EGF-induced EGFR internalization.
abstract: The epidermal growth factor receptor (EGFR) is an important regulator of normal growth and differentiation, and it is involved in the pathogenesis of many cancers. Endocytic downregulation is central in terminating EGFR signaling after ligand stimulation. It has been shown that p38 MAPK activation also can induce EGFR endocytosis. This endocytosis lacks many of the characteristics of ligand-induced EGFR endocytosis. We compared the two types of endocytosis with regard to the requirements for proteins in the internalization machinery. Both types of endocytosis require clathrin, but while epidermal growth factor (EGF)-induced EGFR internalization also required Grb2, p38 MAPK-induced internalization did not. Interestingly, AP-2 knock down blocked p38 MAPK-induced EGFR internalization, but only mildly affected EGF-induced internalization. In line with this, simultaneously mutating two AP-2 interaction sites in EGFR affected p38 MAPK-induced internalization much more than EGF-induced EGFR internalization. Thus, it seems that EGFR in the two situations uses different sets of internalization mechanisms.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Grandal
authors.forename: Lene M
authors.initials: LM
authors.lastname: Grøvdal
authors.forename: Lasse
authors.initials: L
authors.lastname: Henriksen
authors.forename: Mette H
authors.initials: MH
authors.lastname: Andersen
authors.forename: Mikkel R
authors.initials: MR
authors.lastname: Holst
authors.forename: Inger H
authors.initials: IH
authors.lastname: Madshus
authors.forename: Bo
authors.initials: B
authors.lastname: van Deurs
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D033962:Adaptor Protein Complex 2; D051380:GRB2 Adaptor Protein; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases