title: The Dipole Potential Modifies the Clustering and Ligand Binding Affinity of ErbB Proteins and Their Signaling Efficiency.
abstract: Although activation of the ErbB family of receptor tyrosine kinases (ErbB1-4) is driven by oligomerization mediated by intermolecular interactions between the extracellular, the kinase and the transmembrane domains, the transmembrane domain has been largely neglected in this regard. The largest contributor to the intramembrane electric field, the dipole potential, alters the conformation of transmembrane peptides, but its effect on ErbB proteins is unknown. Here, we show by Förster resonance energy transfer (FRET) and number and brightness (N&B) experiments that the epidermal growth factor (EGF)-induced increase in the homoassociation of ErbB1 and ErbB2 and their heteroassociation are augmented by increasing the dipole potential. These effects were even more pronounced for ErbB2 harboring an activating Val → Glu mutation in the transmembrane domain (NeuT). The signaling capacity of ErbB1 and ErbB2 was also correlated with the dipole potential. Since the dipole potential decreased the affinity of EGF to ErbB1, the augmented growth factor-induced effects at an elevated dipole potential were actually induced at lower receptor occupancy. We conclude that the dipole potential plays a permissive role in the clustering of ErbB receptors and that the effects of lipid rafts on ligand binding and receptor signaling can be partially attributed to the dipole potential.
authors: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem square 1, 4032 Debrecen, Hungary.
authors: Tamás
authors: T
authors: Kovács
authors: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem square 1, 4032 Debrecen, Hungary.
authors: Gyula
authors: G
authors: Batta
authors: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem square 1, 4032 Debrecen, Hungary.
authors: Tímea
authors: T
authors: Hajdu
authors: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem square 1, 4032 Debrecen, Hungary.|MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Egyetem square 1, 4032 Hungary.
authors: Ágnes
authors: Á
authors: Szabó
authors: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem square 1, 4032 Debrecen, Hungary.
authors: Tímea
authors: T
authors: Váradi
authors: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem square 1, 4032 Debrecen, Hungary.
authors: Florina
authors: F
authors: Zákány
authors: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem square 1, 4032 Debrecen, Hungary.
authors: István
authors: I
authors: Csomós
authors: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem square 1, 4032 Debrecen, Hungary.|MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Egyetem square 1, 4032 Hungary.
authors: János
authors: J
authors: Szöllősi
authors: Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem square 1, 4032 Debrecen, Hungary.
authors: Peter
authors: P
authors: Nagy
mesh_terms: D002460:Cell Line; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006367:HeLa Cells; D006801:Humans; D007653:Ketocholesterols / Q000737:chemistry / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D010693:Phloretin / Q000737:chemistry / Q000378:metabolism; D017354:Point Mutation; D000072417:Protein Domains; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D007653:Ketocholesterols; D010693:Phloretin; D018719:Erb-b2 Receptor Tyrosine Kinases; D014443:Tyrosine; C063833:6-ketocholestanol; C508053:ERBB2 protein, human