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

Academic Article


  • 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. © 2012, American Society for Microbiology.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Author List

  • Izawa T; Zou W; Chappel JC; Ashley JW; Feng X; Teitelbaum SL
  • Start Page

  • 2943
  • End Page

  • 2953
  • Volume

  • 32
  • Issue

  • 14