A novel recombinant soluble splice variant of met is a potent antagonist of the hepatocyte growth factor/scatter factor-met pathway

Zohar Tiran*, Anat Oren, Chen Hermesh, Galit Rotman, Zurit Levine, Hagit Amitai, Tal Handelsman, Merav Beiman, Aviva Chen, Dalit Landesman-Milo, Liat Dassa, Yair Peres, Cynthia Koifman, Sarit Glezer, Rinat Vidal-Finkelstein, Kobi Bahat, Tania Pergam, Cylia Israel, Judith Horev, Ilan TsarfatyMichal Ayalon-Soffer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: 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. Experimental Design: 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.

Original languageEnglish
Pages (from-to)4612-4621
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number14
DOIs
StatePublished - 15 Jul 2008

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