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Evidence for a Functional Association between Phosphatidylinositol 3-Kinase and c-src in the Spreading Response of Osteoclasts to Colony-Stimulating Factor-1¹

Section of Endocrinology, Yale University, New Haven, Connecticut 06520; and Fred Hutchinson Cancer Research Center (K.C.), Seattle, Washington 98104

Address all correspondence and requests for reprints to: Dr. Karl Insogna, Section of Endocrinology, Yale University School of Medicine, P.O. Box 208020, New Haven, Connecticut 06520-8020. E-mail: karl.insogna{at}yale.edu

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.

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