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

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

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 αvβ33, 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 KB and the macrophage colony-stimulating factor receptor, and also downregulate the signaling from many of these receptors.

Original languageEnglish (US)
Pages (from-to)106-125
Number of pages20
JournalImmunological Reviews
Volume208
StatePublished - Dec 2005
Externally publishedYes

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src-Family Kinases
Osteoclasts
Proteins
Integrins
Macrophage Colony-Stimulating Factor Receptors
Phosphatidylinositol 3-Kinase
Dynamins
Bone and Bones
Cell Polarity
Ubiquitin-Protein Ligases
Bone Development
Gene Deletion
Bone Resorption
Cytoplasmic and Nuclear Receptors
Cell Movement
Homeostasis
Down-Regulation
Phenotype

ASJC Scopus subject areas

  • Immunology

Cite this

The role(s) of Src kinase and Cbl proteins in the regulation of osteoclast differentiation and function. / Horne, William C.; Sanjay, Archana; Bruzzaniti, Angela; Baron, Roland.

In: Immunological Reviews, Vol. 208, 12.2005, p. 106-125.

Research output: Contribution to journalArticle

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