PMID- 10037743
OWN - NLM
STAT- MEDLINE
DCOM- 19990330
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 10
DP  - 1999 Mar 5
TI  - Heparan sulfate-modified CD44 promotes hepatocyte growth factor/scatter 
      factor-induced signal transduction through the receptor tyrosine kinase c-Met.
PG  - 6499-506
AB  - 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.
FAU - van der Voort, R
AU  - van der Voort R
AD  - Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 
      AZ Amsterdam, The Netherlands.
FAU - Taher, T E
AU  - Taher TE
FAU - Wielenga, V J
AU  - Wielenga VJ
FAU - Spaargaren, M
AU  - Spaargaren M
FAU - Prevo, R
AU  - Prevo R
FAU - Smit, L
AU  - Smit L
FAU - David, G
AU  - David G
FAU - Hartmann, G
AU  - Hartmann G
FAU - Gherardi, E
AU  - Gherardi E
FAU - Pals, S T
AU  - Pals ST
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Hyaluronan Receptors)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - 9050-30-0 (Heparitin Sulfate)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Heparitin Sulfate
MH  - Hepatocyte Growth Factor/*pharmacology
MH  - Humans
MH  - Hyaluronan Receptors/chemistry/*metabolism
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-met/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Tumor Cells, Cultured
EDAT- 1999/02/26 00:00
MHDA- 1999/02/26 00:01
CRDT- 1999/02/26 00:00
PHST- 1999/02/26 00:00 [pubmed]
PHST- 1999/02/26 00:01 [medline]
PHST- 1999/02/26 00:00 [entrez]
AID - S0021-9258(19)87612-3 [pii]
AID - 10.1074/jbc.274.10.6499 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Mar 5;274(10):6499-506. doi: 10.1074/jbc.274.10.6499.