title: A novel recombinant soluble splice variant of Met is a potent antagonist of the hepatocyte growth factor/scatter factor-Met pathway.
abstract: OBJECTIVE
  The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), are involved in a wide range of biological activities, including cell proliferation, motility, invasion, and angiogenesis. The HGF/SF-Met signaling pathway is frequently activated in a variety of cancers, and uncontrolled Met activation correlates with highly invasive tumors and poor prognosis. In this study, we investigated the inhibitory effect of a novel soluble splice variant of Met on the HGF/SF-Met pathway.
  
  
  METHODS
  Using our alternative splicing modeling platform LEADS, we have identified a novel splice variant of the Met receptor, which encodes a truncated soluble form of the receptor. This variant was produced as a recombinant Fc-fused protein named Cgen-241A and was tested in various cell-based assays representing different outcomes of the HGF/SF-Met pathway.
  
  
  RESULTS
  Cgen-241A significantly inhibited HGF/SF-induced Met phosphorylation as well as cell proliferation and survival. In addition, Cgen-241A showed a profound inhibitory effect on cell scattering, invasion, and urokinase up-regulation. The inhibitory effects of Cgen-241A were shown in multiple human and nonhuman cell types, representing different modes of Met activation. Furthermore, Cgen-241A showed direct binding to HGF/SF.
  
  
  CONCLUSIONS
  Taken together, our results indicate that Cgen-241A is a potent antagonist of the HGF/SF-Met pathway, underlining its potential as a therapeutic agent for the treatment of a wide variety of human malignancies that are dependent on this pathway.
authors.affiliation: Compugen Ltd., Tel Aviv, Israel. zohar.tiran@cgen.com
authors.forename: Zohar
authors.initials: Z
authors.lastname: Tiran
authors.forename: Anat
authors.initials: A
authors.lastname: Oren
authors.forename: Chen
authors.initials: C
authors.lastname: Hermesh
authors.forename: Galit
authors.initials: G
authors.lastname: Rotman
authors.forename: Zurit
authors.initials: Z
authors.lastname: Levine
authors.forename: Hagit
authors.initials: H
authors.lastname: Amitai
authors.forename: Tal
authors.initials: T
authors.lastname: Handelsman
authors.forename: Merav
authors.initials: M
authors.lastname: Beiman
authors.forename: Aviva
authors.initials: A
authors.lastname: Chen
authors.forename: Dalit
authors.initials: D
authors.lastname: Landesman-Milo
authors.forename: Liat
authors.initials: L
authors.lastname: Dassa
authors.forename: Yair
authors.initials: Y
authors.lastname: Peres
authors.forename: Cynthia
authors.initials: C
authors.lastname: Koifman
authors.forename: Sarit
authors.initials: S
authors.lastname: Glezer
authors.forename: Rinat
authors.initials: R
authors.lastname: Vidal-Finkelstein
authors.forename: Kobi
authors.initials: K
authors.lastname: Bahat
authors.forename: Tania
authors.initials: T
authors.lastname: Pergam
authors.forename: Cylia
authors.initials: C
authors.lastname: Israel
authors.forename: Judith
authors.initials: J
authors.lastname: Horev
authors.forename: Ilan
authors.initials: I
authors.lastname: Tsarfaty
authors.forename: Michal
authors.initials: M
authors.lastname: Ayalon-Soffer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D020349:Surface Plasmon Resonance
chemical_list: D020033:Protein Isoforms; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met