title: c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption.
abstract: The primary defect in mice lacking the c-src gene is osteopetrosis, a deficiency in bone resorption by osteoclasts. Osteoclasts express high levels of the c-Src protein and the defect responsible for the osteopetrotic phenotype of the c-src-deficient (src-) mouse is cell-autonomous and occurs in mature osteoclasts. However, the specific signalling pathways that require c-Src expression for normal osteoclast activity have not been elucidated. We report here that the proto-oncogene product c-Cbl is tyrosine-phosphorylated in a Src-dependent manner in osteoclasts, where the two proteins colocalize on some vesicular structures. In vitro bone resorption by osteoclast-like cells (OCLs) is inhibited by both c-src and c-cbl antisense oligonucleotides. Furthermore, tyrosine phosphorylation of c-Cbl and the localization of c-Cbl-containing structures to the peripheral cytoskeleton are impaired in resorption-deficient c-src- OCLs, as well as in wild-type OCLs that have been treated with c-src antisense oligonucleotides. These results indicate that c-Cbl may act downstream of c-Src in a signalling pathway that is required for bone resorption.
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Amling
authors.forename: L
authors.initials: L
authors.lastname: Neff
authors.forename: A
authors.initials: A
authors.lastname: Peyman
authors.forename: E
authors.initials: E
authors.lastname: Uhlmann
authors.forename: J B
authors.initials: JB
authors.lastname: Levy
authors.forename: R
authors.initials: R
authors.lastname: Baron
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases
chemical_list: D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D016392:Proto-Oncogene Proteins pp60(c-src); C493849:Cbl protein, mouse