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CD44 is required for two consecutive steps in HGF/c-Met signaling
Véronique Orian-Rousseau1, Linfeng Chen, Jonathan P Sleeman
1Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany.
Genes & Development
|December 5, 2002
Summary
Tumor metastasis proteins cooperate: CD44v6 is essential for c-Met receptor activation by HGF/SF, facilitating downstream signaling. This interaction involves ezrin-radixin-moesin proteins and the actin cytoskeleton.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The tyrosine kinase receptor c-Met, its ligand HGF/SF, ezrin, and CD44 splice variants are individually linked to tumor metastasis.
- Independent identification of these proteins suggests potential roles in cancer progression.
Purpose of the Study:
- To investigate the cooperative interactions between c-Met, HGF/SF, ezrin, and CD44 splice variants in tumor metastasis.
- To elucidate the specific role of CD44 variant exon v6 in c-Met activation and downstream signaling.
Main Methods:
- Utilized rat and human carcinoma cell lines and primary keratinocytes.
- Employed CD44v6-deficient cells and transfection with CD44v6-bearing isoforms.
- Applied antibodies targeting v6-encoded epitopes to assess c-Met autophosphorylation.
- Investigated the requirement of the CD44 cytoplasmic tail and ERM protein binding motif for signal transduction.
Main Results:
- A CD44 isoform containing variant exon v6 sequences is indispensable for HGF/SF-mediated c-Met activation.
- CD44v6-deficient cells failed to activate c-Met, which was rescued by CD44v6 reintroduction.
- Antibodies against CD44v6 epitopes disrupted c-Met autophosphorylation by interfering with a c-Met/CD44v6/HGF/SF complex.
- Signal transduction from activated c-Met to MEK and Erk pathways necessitates the CD44 cytoplasmic tail, including an ERM protein binding site.
Conclusions:
- CD44v6 acts as a crucial co-receptor, essential for c-Met activation by HGF/SF in carcinoma cells.
- The interaction highlights a cooperative mechanism involving CD44v6, c-Met, and HGF/SF in promoting tumor metastasis.
- Downstream signaling relies on the CD44 cytoplasmic tail and potentially ezrin-radixin-moesin proteins, linking c-Met activation to the actin cytoskeleton.