title: Metastasis suppressor tetraspanin CD82/KAI1 regulates ubiquitylation of epidermal growth factor receptor.
abstract: Ligand-induced ubiquitylation of EGF receptor (EGFR) is an important regulatory mechanism that controls endocytic trafficking of the receptor and its signaling potential. Here we report that tetraspanin CD82/KAI1 specifically suppresses ubiquitylation of EGFR after stimulation with heparin-binding EGF or amphiregulin and alters the rate of recruitment of the activated receptor to EEA1-positive endosomes. The suppressive effect of CD82 is dependent on the heparin-binding domain of the ligand. Deletion of the C-terminal cytoplasmic domain of CD82 (CD82ΔC mutant) inhibits endocytic trafficking of the tetraspanin and compromises its activity toward heparin-binding EGF-activated EGFR. Reduced ubiquitylation of EGFR is accompanied by PKC-dependent increase in serine phosphorylation of c-Cbl in cells expressing elevated levels of CD82. Furthermore, phosphorylation of threonine 654 (PKC phosphorylation site) in the juxtamembrane domain of the receptor is considerably increased in CD82-expressing cells. These results describe previously unsuspected links between tetraspanin proteins and ubiquitylation of their molecular partners (e.g., EGFR). Our data identify CD82 as a new regulator of c-Cbl, which discriminatively controls the activity of this E3 ubiquitin ligase toward heparin-binding ligand-EGFR pairs. Taken together, these observations provide an important new insight into the modulatory role of CD82 in endocytic trafficking of EGF receptor.
authors.affiliation: From the School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom,. Electronic address: e.odintsova@bham.ac.uk.
authors.forename: Elena
authors.initials: E
authors.lastname: Odintsova
authors.affiliation: the Institut Curie, Centre de Recherche, and Unité Mixte de Recherche 144, Centre National de la Recherche Scientifique, F-75248 Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: van Niel
authors.affiliation: the Matière et Systèmes Complexes, UMR 7057 CNRS, Université Denis Diderot Paris-VII, 75205 Paris, France, and.
authors.forename: Hélène
authors.initials: H
authors.lastname: Conjeaud
authors.affiliation: the Institut Curie, Centre de Recherche, and Unité Mixte de Recherche 144, Centre National de la Recherche Scientifique, F-75248 Paris, France.
authors.forename: Graça
authors.initials: G
authors.lastname: Raposo
authors.affiliation: the Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Iwamoto
authors.affiliation: the Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Mekada
authors.affiliation: From the School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Fedor
authors.initials: F
authors.lastname: Berditchevski
mesh_terms: D066258:Amphiregulin; D002460:Cell Line; D066255:EGF Family of Proteins; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051861:Kangai-1 Protein / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C497688:CD82 protein, human; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D051861:Kangai-1 Protein; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C512478:EGFR protein, human; D066246:ErbB Receptors; D011493:Protein Kinase C; C067419:CBL protein, human
keywords: CD82; Epidermal Growth Factor Receptor (EGFR); Heparin-binding Protein; Tetraspanins; Trafficking; Ubiquitylation
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