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A more recent version of this article appeared on January 1, 2007
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Submitted on August 4, 2006
Revised on September 27, 2006
Accepted on October 13, 2006
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, Postfach 3640, 76021 Karlsruhe, Germany
Monitoring Editor: Carl-Henrik Heldin
In several types of cells the activation of the receptor tyrosine kinase c-Met by its ligand HGF requires the coreceptor CD44v6 (Orian-Rousseau et al., 2002). 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 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 (GEF) Sos. The ERM proteins need, in addition, to be linked to the actin cytoskeleton in order 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.
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)
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