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Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption.
- Source :
-
The Journal of cell biology [J Cell Biol] 2007 Mar 12; Vol. 176 (6), pp. 877-88. - Publication Year :
- 2007
-
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.
- Subjects :
- Amino Acid Motifs
Animals
Bone Resorption pathology
Cell Differentiation
Chimera metabolism
Humans
Integrin alphaVbeta3 metabolism
Intracellular Signaling Peptides and Proteins genetics
Intracellular Signaling Peptides and Proteins metabolism
Mice
Molecular Sequence Data
Osteoclasts pathology
Osteoclasts physiology
Phosphorylation
Protein-Tyrosine Kinases genetics
Protein-Tyrosine Kinases metabolism
Proto-Oncogene Proteins pp60(c-src) metabolism
Receptors, Immunologic chemistry
Receptors, Immunologic metabolism
Sequence Alignment
Syk Kinase
Bone Resorption enzymology
Integrin alphaVbeta3 physiology
Intracellular Signaling Peptides and Proteins physiology
Osteoclasts enzymology
Protein-Tyrosine Kinases physiology
Proto-Oncogene Proteins pp60(c-src) physiology
Receptors, Immunologic physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9525
- Volume :
- 176
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 17353363
- Full Text :
- https://doi.org/10.1083/jcb.200611083