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.

IntroductionAngiogenesis is a complex process that leads to the formation of new blood vessels from existing ones. During embryogenesis, angiogenesis complements vasculogenesis, the production of new blood vessels from hematopoietic precursors. In the adult organism, angiogenesis takes place under normal conditions during the female reproductive cycle or under pathologic conditions, such as in tumor growth and wound healing. Secretion of angiogenic factors from the tumor mass induces the formation of blood vessels, which feed cancer cells with oxygen and nutrients. These vessels will eventually be used as a route for the spreading of metastases. 1 Several angiogenic factors have been described, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor-␣ (TGF-␣), TGF-␤, hepatocyte growth factor (HGF), tumor necrosis factor, angiogenin, interleukin-8, and the angiopoietins. 2 The most prominent angiogenic factor is VEGF-A, a member of the VEGF family of growth factors also including placental growth factor and VEGF-B, -C, -D, and -E. 3 VEGFs bind to 3 related members of the VEGFR family, VEGFR-1, -2, and -3. The importance of VEGFs and their receptors is demonstrated by the phenotypes of the respective knockout mice. Indeed, Vegf-A and Vegfr-2 knockout mice show a failure in vasculature formation and die during embryogenesis, whereas Vegfr-1-deficient mice die of an overgrowth of blood vessels. 3 Fighting angiogenesis has become an attractive aim of cancer therapy. Indeed, targeting angiogenesis rather than directly addressing the tumor cells has the advantage that the same reagents can be applied to many different types of tumors. In addition, because of the low turnover rate of endothelial cells (ECs), they are less susceptible to become resistant to chemotherapy. 4 Several anti-VEGF treatment regimens already exist that can be combined with chemotherapy or radiotherapy. These treatments make use of VEGF inhibitors, such as antibodies against VEGF (bevacizumab), several small molecules inhibiting VEGFR-2 signaling, as well as soluble VEGF receptors that compete with the endogenous receptor for binding to VEGF. 5 However, because all these treatments have a relatively modest benefit for most cancer patients, there is still plenty of room for improvement.HGF is another potent angiogenic factor: the expression of HGF and its receptor c-Met correlates with tumor vascularization, 6 the production of VEGF in a variety of cells and tissues is induced by HGF, 7 and HGF can potentiate the activity of VEGF. [8][9][10] Furthermore, HGF leads to mobilization of endothelial progenitor cells, 11 and the expression of a soluble c-Met receptor (decoy Met) impairs tumor angiogenesis. 12 We have previously shown that HGF depends on a CD44 exon v6 containing isoform for the activation of c-Met on epithelial cells. 13 CD44 isoforms containing the variant exon v6 have been shown to be metastatic determinants. 14 The role of CD44v6 in metastasis results most probably from its coop...

Various human cancers express elevated levels of the receptor tyrosine kinases Met or Ron and v6-containing isoforms of CD44. The activation of Met and Ron requires the presence of such CD44 v6-containing isoforms that act as coreceptors. Three amino acids within the v6 sequence were identified by mutational analysis to be essential for the coreceptor function: EWQ in the rat sequence and RWH in human. Peptides comprising these three amino acids (the smallest containing only five amino acids) efficiently act as competitors and block ligand-dependent activation of Met or Ron and subsequent cell migration. (Cancer Res 2005; 65(14): 6105-10)

CD44v6 acts as a coreceptor for the receptor tyrosine kinases c-Met and VEGFR-2. It is shown that ICAM-1 can act as a new coreceptor in CD44v6-negative tumor cells. Furthermore, ICAM-1 can substitute for CD44v6 as a coreceptor for c-Met in primary hepatocytes and in liver regeneration in Cd44 null mice.

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