C-src links a RANK/αvβ3 integrin complex to the osteoclast cytoskeleton

Takashi Izawa, Wei Zou, Jean C. Chappel, Jason W. Ashley, Xu Feng, Steven L. Teitelbaum

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

RANK ligand (RANKL), by mechanisms unknown, directly activates osteoclasts to resorb bone. Because c-Src is key to organizing the cell's cytoskeleton, we asked if the tyrosine kinase also mediates RANKL-stimulated osteoclast activity. RANKL induces c-Src to associate with RANK369-373 in an αvβ3-dependent manner. Furthermore, RANK369-373 is the only one of six putative TRAF binding motifs sufficient to generate actin rings and activate the same cytoskeleton-organizing proteins as the integrin. While c-Src organizes the cell's cytoskeleton in response to the cytokine, it does not participate in RANKL-stimulated osteoclast formation. Attesting to their collaboration, αvβ3 and activated RANK coprecipitate, but only in the presence of c-Src. c-Src binds activated RANK via its Src homology 2 (SH2) domain and αvβ3 via its SH3 domain, suggesting the kinase links the two receptors. Supporting this hypothesis, deletion or inactivating point mutation of either the c-Src SH2 or SH3 domain obviates the RANK/αvβ3 association. Thus, activated RANK prompts two distinct signaling pathways; one promotes osteoclast formation, and the other, in collaboration with c-Src-mediated linkage to αvβ3, organizes the cell's cytoskeleton.

Original languageEnglish
Pages (from-to)2943-2953
Number of pages11
JournalMolecular and Cellular Biology
Volume32
Issue number14
DOIs
Publication statusPublished - Jul 1 2012
Externally publishedYes

Fingerprint

RANK Ligand
src Homology Domains
Osteoclasts
Cytoskeleton
Integrins
Point Mutation
Protein-Tyrosine Kinases
Actins
Phosphotransferases
Cytokines
Bone and Bones
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Izawa, T., Zou, W., Chappel, J. C., Ashley, J. W., Feng, X., & Teitelbaum, S. L. (2012). C-src links a RANK/αvβ3 integrin complex to the osteoclast cytoskeleton. Molecular and Cellular Biology, 32(14), 2943-2953. https://doi.org/10.1128/MCB.00077-12

C-src links a RANK/αvβ3 integrin complex to the osteoclast cytoskeleton. / Izawa, Takashi; Zou, Wei; Chappel, Jean C.; Ashley, Jason W.; Feng, Xu; Teitelbaum, Steven L.

In: Molecular and Cellular Biology, Vol. 32, No. 14, 01.07.2012, p. 2943-2953.

Research output: Contribution to journalArticle

Izawa, T, Zou, W, Chappel, JC, Ashley, JW, Feng, X & Teitelbaum, SL 2012, 'C-src links a RANK/αvβ3 integrin complex to the osteoclast cytoskeleton', Molecular and Cellular Biology, vol. 32, no. 14, pp. 2943-2953. https://doi.org/10.1128/MCB.00077-12
Izawa, Takashi ; Zou, Wei ; Chappel, Jean C. ; Ashley, Jason W. ; Feng, Xu ; Teitelbaum, Steven L. / C-src links a RANK/αvβ3 integrin complex to the osteoclast cytoskeleton. In: Molecular and Cellular Biology. 2012 ; Vol. 32, No. 14. pp. 2943-2953.
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