c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption.
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.
Mesh Terms:
3T3 Cells, Animals, Bone Resorption, Cells, Cultured, Fibroblasts, Mice, Mice, Knockout, Oligonucleotides, Antisense, Osteoblasts, Osteoclasts, Phosphorylation, Protein Binding, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins pp60(c-src), Signal Transduction, Ubiquitin-Protein Ligases
3T3 Cells, Animals, Bone Resorption, Cells, Cultured, Fibroblasts, Mice, Mice, Knockout, Oligonucleotides, Antisense, Osteoblasts, Osteoclasts, Phosphorylation, Protein Binding, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins pp60(c-src), Signal Transduction, Ubiquitin-Protein Ligases
Nature
Date: Oct. 10, 1996
PubMed ID: 8849724
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