title: c-Src links a RANK/αvβ3 integrin complex to the osteoclast cytoskeleton.
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 RANK(369-373) in an αvβ3-dependent manner. Furthermore, RANK(369-373) 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.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Izawa
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Jean C
authors.initials: JC
authors.lastname: Chappel
authors.forename: Jason W
authors.initials: JW
authors.lastname: Ashley
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
authors.forename: Steven L
authors.initials: SL
authors.lastname: Teitelbaum
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D003599:Cytoskeleton / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D016296:Mutagenesis; D010010:Osteoclasts / Q000378:metabolism* / Q000648:ultrastructure; D054730:Protein Interaction Domains and Motifs; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains; D019061:src-Family Kinases
chemical_list: D039302:Integrin alphaVbeta3; D046912:Multiprotein Complexes; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases