title: Identification of a novel antagonist of the ErbB1 receptor capable of inhibiting migration of human glioblastoma cells.
abstract: BACKGROUND
  Receptors of the ErbB family are involved in the development of various cancers, and the inhibition of these receptors represents an attractive therapeutic concept. Upon ligand binding, ErbB receptors become activated as homo- or heterodimers, leading to the activation of downstream signaling cascades that result in the facilitation of cell proliferation and migration. A region of the extracellular part of the receptor, termed the 'dimerization arm', is important for the formation of receptor dimers and represents an attractive target for the design of ErbB inhibitors.
  
  
  METHODS
  An ErbB1 targeting peptide, termed Herfin-1, was designed based on a model of the tertiary structure of the EGF-EGFR ternary complex. The binding kinetics of this peptide were determined employing surface plasmon resonance analyses. ErbB1-4 expression and phosphorylation in human glioblastoma cell lines U87 and U118 were determined by Western blotting using specific antibodies. Cell proliferation was determined by MTS staining. Cell migration was examined using a Chemotaxis Migration Kit. Neurite outgrowth from primary cerebellar granule neurons was evaluated by fluorescence microscopy and image processing.
  
  
  RESULTS
  The present study shows that Herfin-1 functions as an ErbB1 antagonist. It binds to the extracellular domain of ErbB1 with a KD value of 361 nM. In U87 and U118 cells, both expressing high levels of ErbB1, Herfin-1 inhibits EGF-induced ErbB1 phosphorylation and cell migration. Additionally, Herfin-1 was found to increase neurite outgrowth in cerebellar granule neurons, likely through the inhibition of a sustained weak ErbB1 activation.
  
  
  CONCLUSIONS
  Targeting the ErbB1 receptor dimerization interface is a promising strategy to inhibit receptor activation in ErbB1-expressing glioma cells.
authors.affiliation: Department of Neuroscience and Pharmacology, Protein Laboratory, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark. mikkel.staberg@cpr.ku.dk
authors.forename: Mikkel
authors.initials: M
authors.lastname: Staberg
authors.forename: Christian
authors.initials: C
authors.lastname: Riemer
authors.forename: Ruodan
authors.initials: R
authors.lastname: Xu
authors.forename: Oksana
authors.initials: O
authors.lastname: Dmytriyeva
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bock
authors.forename: Vladimir
authors.initials: V
authors.lastname: Berezin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D008969:Molecular Sequence Data; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010455:Peptides; D004815:Epidermal Growth Factor; D066246:ErbB Receptors