Cytoskeletal organization of the osteoclast (OC), which is central to the capacity of the cell to resorb bone, is induced by occupancy of the αvβ3 integrin or the macrophage colony-stimulating factor (M-CSF) receptor c-Fms. In both circumstances, the tyrosine kinase Syk is an essential signaling intermediary. We demonstrate that Cbl negatively regulates OC function by interacting with SykY317. Expression of nonphosphorylatable SykY317F in primary Syk-/- OCs enhances M-CSF- and αvβ3-induced phosphorylation of the cytoskeleton-organizing molecules, SLP76, Vav3, and PLCγ2, to levels greater than wild type, thereby accelerating the resorptive capacity of the cell. SykY317 suppresses cytoskeletal organization and function while binding the ubiquitin-protein isopeptide ligase Cbl. Consequently, SykY317F abolishes M-CSF- and integrin-stimulated Syk ubiquitination. Thus, Cbl/SykY317 association negatively regulates OC function and therefore is essential for maintenance of skeletal homeostasis.

Original languageEnglish
Pages (from-to)18833-18839
Number of pages7
JournalJournal of Biological Chemistry
Issue number28
StatePublished - Jul 10 2009


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