A novel recombinant soluble splice variant of Met is a potent antagonist of the hepatocyte growth factor/scatter factor-Met pathway.
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.
Tiran
Zohar
Z
Compugen Ltd., Tel Aviv, Israel. zohar.tiran@cgen.com
Oren
Anat
A
Hermesh
Chen
C
Rotman
Galit
G
Levine
Zurit
Z
Amitai
Hagit
H
Handelsman
Tal
T
Beiman
Merav
M
Chen
Aviva
A
Landesman-Milo
Dalit
D
Dassa
Liat
L
Peres
Yair
Y
Koifman
Cynthia
C
Glezer
Sarit
S
Vidal-Finkelstein
Rinat
R
Bahat
Kobi
K
Pergam
Tania
T
Israel
Cylia
C
Horev
Judith
J
Tsarfaty
Ilan
I
Ayalon-Soffer
Michal
M
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
D020033:Protein Isoforms; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met