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J Biol Chem, Vol. 274, Issue 10, 6499-6506, March 5, 1999
From the Department of Pathology, Academic Medical Center,
University of Amsterdam, 1105 AZ Amsterdam, The Netherlands, the
§ Center for Human Genetics and Flanders Interuniversity
Institute for Biotechnology, University of Leuven, B-3000 Leuven,
Belgium, and the ¶ Growth Factors Group, Department of
Oncology, University of Cambridge,
Cambridge CB2 2QH, United Kingdom
CD44 has been implicated in tumor progression and
metastasis, but the mechanism(s) involved is as yet poorly understood.
Recent studies have shown that 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 functional interaction
between CD44 and hepatocyte growth factor/scatter factor (HGF/SF), the
ligand of the receptor tyrosine kinase c-Met. The HGF/SF-c-Met pathway
mediates cell growth and motility and has been implicated in tumor
invasion and metastasis. We demonstrate that a CD44v3 splice variant
efficiently binds HGF/SF via its heparan sulfate side chain. To address
the functional relevance of this interaction, Namalwa Burkitt's
lymphoma cells were 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 ERK1 and -2. By
heparitinase treatment and the use of a mutant HGF/SF with greatly
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 CD44 (CD44-HS) as a functional co-receptor for HGF/SF which promotes signaling through the receptor tyrosine kinase c-Met, presumably by
concentrating and presenting HGF/SF. As both CD44-HS and c-Met are
overexpressed on several types of tumors, we propose that the observed
functional collaboration might be instrumental in promoting tumor
growth and metastasis.
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