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Vol. 18, Issue 1, 76-83, January 2007
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Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, 76021 Karlsruhe, Germany
Submitted August 4, 2006;
Revised September 27, 2006;
Accepted October 13, 2006
Monitoring Editor: Carl-Henrik Heldin
In several types of cells, the activation of the receptor tyrosine kinase c-Met by its ligand hepatocyte growth factor (HGF) requires the coreceptor CD44v6. The CD44 extracellular domain is necessary for c-Met autophosphorylation, whereas the intracellular domain is required for signal transduction. We have already shown that the CD44 cytoplasmic tail recruits ezrin, radixin and moesin (ERM) proteins to the complex of CD44v6, c-Met, and HGF. We have now defined the function of the ERM proteins and the step they promote in the signaling cascade. The association of ERM proteins to the coreceptor is absolutely required to mediate the HGF-dependent activation of Ras by the guanine nucleotide exchange factor Sos. The ERM proteins need, in addition, to be linked to the actin cytoskeleton to catalyze the activation of Ras. Thus, we describe here a new function of the cytoskeleton. It is part of a "signalosome" complex that organizes the activation of Ras by Sos. So far the cytoskeleton has mainly been identified as a "responder" to signal transduction. Here, we show now that F-actin acts as an "inducer" that actively organizes the signaling cascade.
* These authors contributed equally to this work.
Present address: Leibniz Institute for Age Research-Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
Address correspondence to: Helmut Ponta (helmut.ponta{at}itg.fzk.de)
Abbreviations used: ERM, ezrin, radixin, moesin; HGF, hepatocyte growth factor/scatter factor; RTK, receptor tyrosine kinase.
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