Heparan sulfate-modified CD44 promotes hepatocyte growth factor scatter factor induced signal transduction through the receptor tyrosine kinase c-Met

CD44 has been implicated in tumor progression and metastasis, but the mecha nism(s) involved is as yet poorly understood. Recent studies have shown tha t CD44 isoforms containing the alternatively spliced exon v3 carry heparan sulfate side chains and are able to bind heparin-binding growth factors. In the present study, we have explored the possibility of a physical and func tional interaction between CD44 and hepatocyte growth factor/scatter factor (HGF/SF), the ligand of the receptor tyrosine kinase c-Met. The HGF/SF-c-M et pathway mediates cell growth and motility and has been implicated in tum or invasion and metastasis. We demonstrate that a CD44v3 splice variant eff iciently binds HGF/SF via its heparan sulfate side chain. To address the fu nctional relevance of this interaction, Namalwa Burkitt's lymphoma cells we re stably co-transfected with c-Met and either CD44v3 or the isoform CD44s, which lacks heparan sulfate. We show that, as compared with CD44s, CD44v3 promotes: (i) HGF/SF-induced phosphorylation of c-Met, (ii) phosphorylation of several downstream proteins, and (iii) activation of the MAP kinases ER K1 and -2, By heparitinase treatment and the use of a mutant HGF/SF with gr eatly decreased affinity for heparan sulfate, we show that the enhancement of c-Met signal transduction induced by CD44v3 was critically dependent on heparan sulfate moieties, Our results identify heparan sulfate-modified CD4 4 (CD44-HS) as a functional co-receptor for HGF/SF which promotes signaling through the receptor tyrosine kinase c-Met, presumably by concentrating an d presenting HGF/SF. As both CD44-HS and c-Met are overexpressed on several types of tumors, we propose that the observed functional collaboration mig ht be instrumental in promoting tumor growth and metastasis.