CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration.
In this study we have demonstrated that both CD44 (the hyaluronan (HA) receptor) and c-Src kinase are expressed in human ovarian tumor cells (SK-OV-3.ipl cell line), and that these two proteins are physically associated as a complex in vivo. Using a recombinant cytoplasmic domain of CD44 and an in vitro ... binding assay, we have detected a specific interaction between CD44 and c-Src kinase. Furthermore, the binding of HA to SK-OV-3.ipl cells promotes c-Src kinase recruitment to CD44 and stimulates c-Src kinase activity, which, in turn, increases tyrosine phosphorylation of the cytoskeletal protein, cortactin. Subsequently, tyrosine phosphorylation of cortactin attenuates its ability to cross-link filamentous actin in vitro. In addition, transfection of SK-OV-3.ipl cells with a dominant active form of c-Src (Y527F)cDNA promotes CD44 and c-Src association with cortactin in membrane projections, and stimulates HA-dependent/CD44-specific ovarian tumor cell migration. Finally, overexpression of a dominant-negative mutant of c-Src kinase (K295R) in SK-OV-3.ipl cells impairs the tumor cell-specific phenotype. Taken together, these findings strongly suggest that CD44 interaction with c-Src kinase plays a pivotal role in initiating cortactin-regulated cytoskeleton function and HA-dependent tumor cell migration, which may be required for human ovarian cancer progression.
Mesh Terms:
Animals, Antigens, CD44, Cell Movement, Cloning, Molecular, Cortactin, Cytoskeleton, DNA, Complementary, Female, Genes, Dominant, Humans, Hyaluronic Acid, Immunoblotting, Microfilament Proteins, Microscopy, Fluorescence, Mutation, Ovarian Neoplasms, Phenotype, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins pp60(c-src), Rats, Recombinant Proteins, Time Factors, Transfection, Tumor Cells, Cultured, Tyrosine
Animals, Antigens, CD44, Cell Movement, Cloning, Molecular, Cortactin, Cytoskeleton, DNA, Complementary, Female, Genes, Dominant, Humans, Hyaluronic Acid, Immunoblotting, Microfilament Proteins, Microscopy, Fluorescence, Mutation, Ovarian Neoplasms, Phenotype, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins pp60(c-src), Rats, Recombinant Proteins, Time Factors, Transfection, Tumor Cells, Cultured, Tyrosine
J. Biol. Chem.
Date: Mar. 09, 2001
PubMed ID: 11084024
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