title: Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption.
abstract: In this study, we establish that the tyrosine kinase Syk is essential for osteoclast function in vitro and in vivo. Syk(-/-) osteoclasts fail to organize their cytoskeleton, and, as such, their bone-resorptive capacity is arrested. This defect results in increased skeletal mass in Syk(-/-) embryos and dampened basal and stimulated bone resorption in chimeric mice whose osteoclasts lack the kinase. The skeletal impact of Syk deficiency reflects diminished activity of the mature osteoclast and not impaired differentiation. Syk regulates bone resorption by its inclusion with the alpha v beta3 integrin and c-Src in a signaling complex, which is generated only when alpha v beta3 is activated. Upon integrin occupancy, c-Src phosphorylates Syk. Alpha v beta3-induced phosphorylation of Syk and the latter's capacity to associate with c-Src is mediated by the immunoreceptor tyrosine-based activation motif (ITAM) proteins Dap12 and FcRgamma. Thus, in conjunction with ITAM-bearing proteins, Syk, c-Src, and alpha v beta3 represent an essential signaling complex in the bone-resorbing osteoclast, and, therefore, each is a candidate therapeutic target.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Hideki
authors.initials: H
authors.lastname: Kitaura
authors.forename: Jennifer
authors.initials: J
authors.lastname: Reeve
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
authors.forename: Victor L J
authors.initials: VL
authors.lastname: Tybulewicz
authors.forename: Sanford J
authors.initials: SJ
authors.lastname: Shattil
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
authors.forename: F Patrick
authors.initials: FP
authors.lastname: Ross
authors.forename: Steven L
authors.initials: SL
authors.lastname: Teitelbaum
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001862:Bone Resorption / Q000201:enzymology* / Q000473:pathology; D002454:Cell Differentiation; D002678:Chimera / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000201:enzymology* / Q000473:pathology / Q000502:physiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism / Q000502:physiology*; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D016415:Sequence Alignment; D000072377:Syk Kinase
chemical_list: D039302:Integrin alphaVbeta3; D047908:Intracellular Signaling Peptides and Proteins; D011971:Receptors, Immunologic; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse