CD44 is required for two consecutive steps in HGF/c-Met signaling.
The tyrosine kinase receptor c-Met and its ligand HGF/SF, ezrin, and splice variants of CD44 have independently been identified as tumor metastasis-associated proteins. We now show that these proteins cooperate. A CD44 isoform containing variant exon v6 sequences is strictly required for c-Met activation by HGF/SF in rat and human carcinoma cells, in established cell lines as well as in primary keratinocytes. CD44v6-deficient tumor cells were unable to activate c-Met unless they were transfected with a CD44v6-bearing isoform. Antibodies to two v6-encoded epitopes inhibited autophosphorylation of c-Met by interfering with the formation of a complex formed by c-Met, CD44v6, and HGF/SF. In addition, signal transduction from activated c-Met to MEK and Erk required the presence of the cytoplasmic tail of CD44 including a binding motif for ERM proteins. This suggests a role for ERM proteins and possibly their link to the cortical actin cytoskeleton in signal transfer.
Orian-Rousseau
Véronique
V
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany.
Chen
Linfeng
L
Sleeman
Jonathan P
JP
Herrlich
Peter
P
Ponta
Helmut
H
D000230:Adenocarcinoma; D002460:Cell Line; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes; D020033:Protein Isoforms / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D006497:Heparan Sulfate; D017228:Hepatocyte Growth Factor; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D019859:Proto-Oncogene Proteins c-met