title: The oncoprotein ErbB3 is endocytosed in the absence of added ligand in a clathrin-dependent manner.
abstract: The oncoprotein ErbB3 is overexpressed in several human cancers, for example in pancreatic adenocarcinoma and in ovarian cancers, and ErbB3-containing heterodimers have been demonstrated to be potent signaling units in carcinogenesis. This especially applies to ErbB2-ErbB3 and epidermal growth factor receptor (EGFR)-ErbB3 heterodimers providing anti-apoptotic signaling. Relatively little is understood about the signaling of EGFR-ErbB3 heterodimers and especially about mechanisms involved in downregulation of ErbB3 from the plasma membrane. This is in contrast to EGFR homodimers, for which trafficking has been extensively characterized. In the present study, we have investigated mechanisms involved in endocytosis of ErbB3 in porcine aortic endothelial cells stably expressing either ErbB3 only or stably expressing ErbB3 and EGFR. Our data show that ErbB3 is endocytosed in the absence of added ligand, independently of its tyrosine phosphorylation state and in a clathrin-dependent manner. Functional EGFR-ErbB3 heterodimers were observed to be formed, and dimerization with ErbB3 was observed to negatively affect endocytosis of the EGFR.
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Rikshospitalet, 0027 Oslo, Norway.
authors.forename: Malgorzata Magdalena
authors.initials: MM
authors.lastname: Sak
authors.forename: Kamilla
authors.initials: K
authors.lastname: Breen
authors.forename: Sissel Beate
authors.initials: SB
authors.lastname: Rønning
authors.forename: Nina Marie
authors.initials: NM
authors.lastname: Pedersen
authors.forename: Vibeke
authors.initials: V
authors.lastname: Bertelsen
authors.forename: Espen
authors.initials: E
authors.lastname: Stang
authors.forename: Inger Helene
authors.initials: IH
authors.lastname: Madshus
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism*; D019281:Dimerization; D004705:Endocytosis; D042783:Endothelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D006367:HeLa Cells; D006420:Hemeproteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013552:Swine; D014407:Tumor Cells, Cultured
chemical_list: D002966:Clathrin; D066246:ErbB Receptors; D006420:Hemeproteins; D008024:Ligands; D015513:Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C546602:SLC48A1 protein, human; C512478:EGFR protein, human