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Submitted on May 19, 2003
Accepted on August 4, 2003
1 Department of Bone Biology and Osteoporosis Research (I.N., G.A.R., L.T.D.), Merck Research Laboratories, West Point, Pennsylvania 19486, USA, Department of Rheumatology (I.N.), Yugawara Kosei-nenkin Hospital, 438 Miyakami, Yugawara, Ashigara-shimo, Kanagawa 259-0314, Japan
* To whom correspondence should be addressed. E-mail: Ichiclast{at}aol.com.
Both p130Cas 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 is to examine adhesion- and 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 p130Cas and c-Cbl in osteoclast function. Cell attachment of normal pOCs to vitronectin induces tyrosine phosphorylation of p130Cas and to the much lesser extent of c-Cbl. Treatment with M-CSF results in further tyrosine phosphorylation of both p130Cas and c-Cbl, suggesting cooperation between 
v
3 integrin and M-CSF receptor, c-Fms, in osteoclasts. However, M-CSF induces tyrosine phosphorylation of c-Cbl, but not p130Cas in pOCs in suspension, confirming the role of c-Cbl as a down stream effector of c-Fms. This observation also suggests that M-CSF-mediated p130Cas phosphorylation requires ligand engagement of v3 integrin. In Src-deficient pOCs plated on vitronectin, while M-CSF highly induces Cbl phosphorylation, it does not affect p130Cas phosphorylation. These results suggest that in osteoclasts, 1) Tyrosine phosphorylation of p130Cas depends on v3 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 independent of cell adhesion; 3) Lastly, while c-Src is essential for both adhesion- and M-CSF-mediated phosphorylation of p130Cas it is clearly not required for c-Cbl phosphorylation in M-CSF-treated pOCs. Taken together, p130Cas and c-Cbl play distinct roles in the signal transduction pathways which mediate cytoskeletal organization in osteoclasts.
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