Evidence for a functional association between phosphatidylinositol 3-kinase and c-src in the spreading response of osteoclasts to colony-stimulating factor-1

Endocrinology. 2000 Jun;141(6):2129-38. doi: 10.1210/endo.141.6.7480.


Osteoclasts are bone-resorbing cells whose normal function depends in part upon their ability to migrate over the bone surface to initiate new sites of bone resorption. The growth factor/cytokine, colony-stimulating factor-1 (CSF-1), potently stimulates osteoclast motility, in a c-src-dependent fashion. The intracellular signaling molecules that participate with c-src in CSF-1-induced remodeling of the osteoclast cytoskeleton have not been identified. Here we demonstrate, using the inhibitors wortmannin and LY294002, that activation of phosphatidylinositol 3-kinase (PI3-K) is required for CSF-1-induced spreading in osteoclasts. After CSF-1 treatment of osteoclast-like cells, PI3-K activity associated with the CSF-1 receptor c-fms, is increased, and the 85-kDa regulatory subunit of PI3-K and c-src coimmunoprecipitate. CSF-1 induces redistribution of PI3-K to the periphery of the cell. The association between p85 and c-src is due in part to a direct interaction between the proline-rich sequences of p85 and the SH3 domain of c-src. In vitro, the c-src SH3 domain stimulates PI3-K activity. Taken together, the current data suggest that c-src, via its SH3 domain, may participate in CSF-1-induced activation of PI3-K and that PI3-K and c-src are in the signaling pathway that subserves CSF-1-induced cytoskeletal changes in osteoclasts.

Publication types

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

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Binding Sites
  • Cell Movement
  • Chromones / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Immunosorbent Techniques
  • Macrophage Colony-Stimulating Factor / pharmacology*
  • Mice
  • Morpholines / pharmacology
  • Osteoclasts / cytology*
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Proline
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • Rats
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism
  • Regulatory Sequences, Nucleic Acid
  • Wortmannin
  • src Homology Domains


  • Androstadienes
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Macrophage Colony-Stimulating Factor
  • Proline
  • Receptor, Macrophage Colony-Stimulating Factor
  • Proto-Oncogene Proteins pp60(c-src)
  • Wortmannin