CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration

J Biol Chem. 2001 Mar 9;276(10):7327-36. doi: 10.1074/jbc.M006498200. Epub 2000 Nov 17.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Movement
  • Cloning, Molecular
  • Cortactin
  • Cytoskeleton / metabolism*
  • DNA, Complementary / metabolism
  • Female
  • Genes, Dominant
  • Humans
  • Hyaluronan Receptors / chemistry*
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Hyaluronic Acid / pharmacology*
  • Immunoblotting
  • Microfilament Proteins / metabolism*
  • Microscopy, Fluorescence
  • Mutation
  • Ovarian Neoplasms / metabolism*
  • Phenotype
  • Phosphorylation
  • Plasmids / metabolism
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • Rats
  • Recombinant Proteins / metabolism
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured
  • Tyrosine / metabolism

Substances

  • CTTN protein, human
  • Cortactin
  • Cttn protein, rat
  • DNA, Complementary
  • Hyaluronan Receptors
  • Microfilament Proteins
  • Recombinant Proteins
  • Tyrosine
  • Hyaluronic Acid
  • Proto-Oncogene Proteins pp60(c-src)