Syk tyrosine 317 negatively regulates osteoclast function via the ubiquitin-protein isopeptide ligase activity of Cbl

Wei Zou, Jennifer L. Reeve, Haibo Zhao, F. Patrick Ross, Steven L. Teitelbaum

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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
Volume284
Issue number28
DOIs
StatePublished - Jul 10 2009

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