Hepatocyte growth factor-induced Ras activation requires ERM proteins linked to both CD44v6 and F-actin.
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.
Orian-Rousseau
Véronique
V
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, 76021 Karlsruhe, Germany.
Morrison
Helen
H
Matzke
Alexandra
A
Kastilan
Thor
T
Pace
Giuseppina
G
Herrlich
Peter
P
Ponta
Helmut
H
D000199:Actins / Q000378:metabolism*; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism*; D019073:HT29 Cells; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D020664:Son of Sevenless Proteins / Q000378:metabolism; D000099149:Ezrin
D000199:Actins; D003598:Cytoskeletal Proteins; D006023:Glycoproteins; D017228:Hepatocyte Growth Factor; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D008840:Microfilament Proteins; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D020664:Son of Sevenless Proteins; D000099149:Ezrin; C112697:CD44v6 antigen; C071058:moesin; C071776:radixin