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.

Cloning and Characterization of a Novel Adaptor Protein, CIN85, That Interacts with c-Cbl

“…Consistent with these findings, functional studies of c-Cbl using mammalian cells have provided additional evidence that c-Cbl may negatively regulate the mammalian tyrosine kinase-mediated signaling pathways [41][42][43][44]. However, experiments using osteoclast has provided another line of evidence that c-Cbl has a positive regulatory role in the c-Src-mediated signaling pathway responsible for bone resorption [45]. These findings indicate that c-Cbl plays a versatile role in a diverse array of intracellular signaling pathways.…”

Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl

“…This suggests a pivotal role in early events following signal transduction across the cell membrane into the cytoplasm. Furthermore, Cbl has been found to associate constitutively or inductively with many signalling proteins such as the Grb2, Crk and Nck adaptor proteins, members of the Src, Abl and Syk tyrosine kinase families, the p85 regulatory subunit of PI 3-kinase and 14-3-3 proteins (Donovan et al, 1994;de Jong et al, 1995;Buday et al, 1996;RiveroLezcano et al, 1994;Ribon et al, 1996;Andoniou et al, 1994Andoniou et al, , 1996Smit et al, 1996;Tanaka et al, 1996;Tsygankov et al, 1996;Fournel et al, 1996;Kim et al, 1995;Meisner et al, 1995;Solto and Cantley, 1996;Liu et al, 1996). To date however a de®nite function for Cbl has not emerged from these studies.…”

c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor

“…In addition to ErbB-1, the receptors for CSF-1 , PDGF (Mori et al 1995), and the scatter factor (Jeffers et al 1997) are also candidates for c-Cbl-mediated down-regulation through a ubiquitin-dependent process. Moreover, c-Cbl may control also nonreceptor tyrosine kinases, such as Syk (Ota and Samelson 1997), and Src (Tanaka et al 1996). If verified, this function may account for the ubiquitous expression of c-Cbl, and for its general involvement in apparently unrelated signaling pathways.…”