title: Dynamic analysis of the epidermal growth factor (EGF) receptor-ErbB2-ErbB3 protein network by luciferase fragment complementation imaging.
abstract: ErbB3 is a member of the ErbB family of receptor tyrosine kinases. It is unique because it is the only member of the family whose kinase domain is defective. As a result, it is obliged to form heterodimers with other ErbB receptors to signal. In this study, we characterized the interaction of ErbB3 with the EGF receptor and ErbB2 and assessed the effects of Food and Drug Administration-approved therapeutic agents on these interactions. Our findings support the concept that ErbB3 exists in preformed clusters that can be dissociated by NRG-1β and that it interacts with other ErbB receptors in a distinctly hierarchical fashion. Our study also shows that all pairings of the EGF receptor, ErbB2, and ErbB3 form ligand-independent dimers/oligomers. The small-molecule tyrosine kinase inhibitors erlotinib and lapatinib differentially enhance the dimerization of the various ErbB receptor pairings, with the EGFR/ErbB3 heterodimer being particularly sensitive to the effects of erlotinib. The data suggest that the physiological effects of these drugs may involve not only inhibition of tyrosine kinase activity but also a dynamic restructuring of the entire network of receptors.
authors.affiliation: From the Departments of Biochemistry and Molecular Biophysics.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Macdonald-Obermann
authors.affiliation: From the Departments of Biochemistry and Molecular Biophysics.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Adak
authors.affiliation: the Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida 33101.
authors.forename: Ralf
authors.initials: R
authors.lastname: Landgraf
authors.affiliation: Cell Biology and Physiology, and; Developmental Biology,; the Mallinckrodt Institute of Radiology, and; the Bridging Research with Imaging, Genomics and High Throughput Technologies Institute, Washington University School of Medicine, St. Louis, Missouri 63110 and.
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.affiliation: From the Departments of Biochemistry and Molecular Biophysics,. Electronic address: pike@biochem.wustl.edu.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Pike
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D000077341:Lapatinib; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077341:Lapatinib; D008156:Luciferases; D009097:Multienzyme Complexes; D020890:Neuregulin-1; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C094131:NRG1 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: Cancer Biology; Epidermal Growth Factor (EGF); Epidermal Growth Factor Receptor (EGFR); ErbB2; ErbB3; Growth Factors; Receptor Tyrosine Kinase