The role(s) of Src kinase and Cbl proteins in the regulation of osteoclast differentiation and function
William C. Horne,
Archana Sanjay,
Angela Bruzzaniti,
Roland Baron,
William C. Horne
Departments of Orthopaedics and Rehabilitation and Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
Search for more papers by this authorArchana Sanjay
Departments of Orthopaedics and Rehabilitation and Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
Department of Anatomy and Physiology, Temple University School of Medicine, Philadelphia, PA, USA.
Search for more papers by this authorAngela Bruzzaniti
Departments of Orthopaedics and Rehabilitation and Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
Search for more papers by this authorCorresponding Author
Roland Baron
Departments of Orthopaedics and Rehabilitation and Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
* Roland Baron Department of Orthopaedics Yale University School of Medicine PO Box 208044 New Haven, CT 06520-8044 USA Tel.: +1 203 785 5986 Fax: +1 203 785 2744 E-mail: [email protected]Search for more papers by this authorWilliam C. Horne,
Archana Sanjay,
Angela Bruzzaniti,
Roland Baron,
William C. Horne
Departments of Orthopaedics and Rehabilitation and Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
Search for more papers by this authorArchana Sanjay
Departments of Orthopaedics and Rehabilitation and Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
Department of Anatomy and Physiology, Temple University School of Medicine, Philadelphia, PA, USA.
Search for more papers by this authorAngela Bruzzaniti
Departments of Orthopaedics and Rehabilitation and Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
Search for more papers by this authorCorresponding Author
Roland Baron
Departments of Orthopaedics and Rehabilitation and Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
* Roland Baron Department of Orthopaedics Yale University School of Medicine PO Box 208044 New Haven, CT 06520-8044 USA Tel.: +1 203 785 5986 Fax: +1 203 785 2744 E-mail: [email protected]Search for more papers by this authorAbstract
Summary: The osteoclast resorbs mineralized bone during bone development, homeostasis, and repair. The deletion of the gene encoding the nonreceptor tyrosine kinase c-Src produces an osteopetrotic skeletal phenotype that is the consequence of the inability of the mature osteoclast to efficiently resorb bone. Src–/– osteoclasts exhibit reduced motility and abnormal organization of the apical secretory domain (the ruffled border) and attachment-related cytoskeletal elements that are necessary for bone resorption. A key function of Src in osteoclasts is to promote the rapid assembly and disassembly of the podosomes, the specialized integrin-based attachment structures of osteoclasts and other highly motile cells. Once recruited to the activated integrins, especially αvβ3, by the adhesion tyrosine kinase Pyk2, Src binds and phosphorylates Cbl and Cbl-b, homologous multisite adapter proteins with ubiquitin ligase activity. The Cbl proteins in turn recruit and activate additional signaling effectors, including phosphatidylinositol 3-kinase and dynamin, which play key roles in the development of cell polarity and the regulation of cell attachment and motility. In addition, Src and the Cbl proteins contribute to signaling cascades that are activated by several important receptors, including receptor activator of nuclear factor κB and the macrophage colony-stimulating factor receptor, and also downregulate the signaling from many of these receptors.
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