CD44 stimulation by fragmented hyaluronic acid induces upregulation and tyrosine phosphorylation of c-Met receptor protein in human chondrosarcoma cells

Biochim Biophys Acta. 2002 Aug 19;1591(1-3):37-44. doi: 10.1016/s0167-4889(02)00246-x.

Abstract

Hepatocyte growth factor/scatter factor (HGF/SF) can induce proliferation and motility and promote invasion of tumor cells. Since HGF/SF receptor, c-Met, is expressed by tumor cells, and since stimulation of CD44, a transmembrane glycoprotein known to bind hyaluronic acid (HA) in its extracellular domain, is involved in activation of c-Met, we have studied the effects of CD44 stimulation by ligation with HA upon the expression and tyrosine phosphorylation of c-Met on human chondrosarcoma cell line HCS-2/8. The current study indicates that (a) CD44 stimulation by fragmented HA upregulates expression of c-Met proteins; (b) fragmented HA also induces tyrosine phosphorylation of c-Met protein within 30 min, an early event in this pathway as shown by the early time course of stimulation; (c) the effects of HA fragments are critically HA size-dependent. High molecular weight HA is inactive, but lower molecular weight fragments (M(r) 3.5 kDa) are active with maximal effect in the microg/ml range; (d) the standard form of CD44 (CD44s) is critical for the response because the effect on c-Met, both in terms of upregulation and phosphorylation, is inhibited by preincubation with an anti-CD44 monoclonal antibody; and (e) phosphorylation of c-Met induced by CD44 stimulation is inhibited by protein tyrosine kinase inhibitor, tyrphostin. Therefore, our study represents the first report that CD44 stimulation induced by fragmented HA enhances c-Met expression and tyrosine phosphorylation in human chondrosarcoma cells. Taken together, these studies establish a signal transduction cascade or cross-talk emanating from CD44 to c-Met.

MeSH terms

  • Chondrosarcoma / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Hyaluronic Acid / metabolism*
  • Hyaluronic Acid / pharmacology
  • Phosphorylation
  • Proto-Oncogene Proteins c-met / metabolism*
  • Tumor Cells, Cultured
  • Tyrosine / metabolism*
  • Up-Regulation / drug effects

Substances

  • Hyaluronan Receptors
  • Tyrosine
  • Hyaluronic Acid
  • Proto-Oncogene Proteins c-met