Syk tyrosine 317 negatively regulates osteoclast function via the ubiquitin-protein isopeptide ligase activity of Cbl.
Cytoskeletal organization of the osteoclast (OC), which is central to the capacity of the cell to resorb bone, is induced by occupancy of the alphavbeta3 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 Syk(Y317). Expression of nonphosphorylatable Syk(Y317F) in primary Syk(-/-) OCs enhances M-CSF- and alphavbeta3-induced phosphorylation of the cytoskeleton-organizing molecules, SLP76, Vav3, and PLCgamma2, to levels greater than wild type, thereby accelerating the resorptive capacity of the cell. Syk(Y317) suppresses cytoskeletal organization and function while binding the ubiquitin-protein isopeptide ligase Cbl. Consequently, Syk(Y317F) abolishes M-CSF- and integrin-stimulated Syk ubiquitination. Thus, Cbl/Syk(Y317) association negatively regulates OC function and therefore is essential for maintenance of skeletal homeostasis.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Wei
W
Zou
Jennifer L
JL
Reeve
Haibo
H
Zhao
F Patrick
FP
Ross
Steven L
SL
Teitelbaum
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D006706:Homeostasis; D016023:Integrins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010010:Osteoclasts / Q000378:metabolism*; D010453:Peptide Synthases / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D000072377:Syk Kinase; D014443:Tyrosine / Q000737:chemistry*; D025801:Ubiquitin / Q000737:chemistry*
D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D025801:Ubiquitin; D014443:Tyrosine; D016173:Macrophage Colony-Stimulating Factor; D050721:Proto-Oncogene Proteins c-cbl; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D010453:Peptide Synthases