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Distinct Roles of p130^Cas and c-Cbl in Adhesion-Induced or Macrophage Colony-Stimulating Factor-Mediated Signaling Pathways in Prefusion Osteoclasts

Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories (I.N., G.A.R., L.T.D.), West Point, Pennsylvania 19486; and Department of Rheumatology, Yugawara Kosei-nenkin Hospital (I.N.), Yugawara, Ashigara-shimo, Kanagawa 259-0314, Japan

Address all correspondence and requests for reprints to: Dr. Ichiro Nakamura, Department of Rheumatology, Yugawara Kosei-nenkin Hospital, 438 Miyakami, Yugawara, Ashigara-shimo, Kanagawa 259-0314, Japan. E-mail: ichiclast{at}aol.com.

Abstract

Both p130^Cas and c-Cbl have been reported to play critical roles in osteoclast function as downstream targets of c-Src kinase. The purpose of this study was to examine adhesion- and macrophage colony-stimulating factor (M-CSF)-induced tyrosine phosphorylation of these two molecules in prefusion osteoclasts (pOCs) derived from either Src^+/? or Src^-/- mice and to directly compare the roles of p130^Cas and c-Cbl in osteoclast function. Cell attachment of normal pOCs to vitronectin induces tyrosine phosphorylation of p130^Cas and, to a much lesser extent, of c-Cbl. Treatment with M-CSF results in further tyrosine phosphorylation of both p130^Cas and c-Cbl, suggesting cooperation between _vß₃ integrin and the M-CSF receptor, c-Fms, in osteoclasts. However, M-CSF induces tyrosine phosphorylation of c-Cbl, but not p130^Cas in pOCs in suspension, confirming the role of c-Cbl as a downstream effector of c-Fms. This observation also suggests that M-CSF-mediated p130^Cas phosphorylation requires ligand engagement of _vß₃ integrin. In Src-deficient pOCs plated on vitronectin, although M-CSF highly induces Cbl phosphorylation, it does not affect p130^Cas phosphorylation. These results suggest that in osteoclasts 1) tyrosine phosphorylation of p130^Cas depends on _vß₃ integrin-mediated cell adhesion, even in the presence of M-CSF; 2) on the other hand, c-Cbl phosphorylation is predominantly activated by M-CSF and is independent of cell adhesion; 3) lastly, although c-Src is essential for both adhesion- and M-CSF-mediated phosphorylation of p130^Cas, it is clearly not required for c-Cbl phosphorylation in M-CSF-treated pOCs. Taken together, p130^Cas and c-Cbl play distinct roles in the signal transduction pathways that mediate cytoskeletal organization in osteoclasts.

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