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 osteoclasts1. Osteoclasts express high levels of the c-Src protein2,3 and the defect responsible for the osteopetrotic phenotype of the c-src-deficient (src) mouse is cell-autonomous and occurs in mature osteoclasts4,5. 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 oligonucleo-tides. Furthermore, tryosine 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.

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References

  1. 1

    Soriano, P., Montgomery, C., Geske, R. & Bradley, A. Cell 64, 693–702 (1991).

    CAS  Article  Google Scholar 

  2. 2

    Horne, W. C. et al. J. Cell Biol. 119, 1003–1013 (1992).

    ADS  CAS  Article  Google Scholar 

  3. 3

    Tanaka, S. et al. FEBS Lett. 313, 85–89 (1992).

    CAS  Article  Google Scholar 

  4. 4

    Boyce, B. F., Yoneda, T., Lowe, C., Soriano, P. & Mundy, G. R. J. Clin. Invest. 90, 1622–1627 (1992).

    CAS  Article  Google Scholar 

  5. 5

    Lowe, C. et al. Proc. Natl Acad. Sci. USA 90, 4485–4489 (1993).

    ADS  CAS  Article  Google Scholar 

  6. 6

    Tanaka, S., Neff, L., Baron, R. & Levy, J. B. J. Biol. Chem. 270, 14347–14351 (1995).

    CAS  Article  Google Scholar 

  7. 7

    Donovan, J. A., Wange, R. L., Langdon, W. Y. & Samelson, L. E. J. Biol. Chem. 269, 22921–22924 (1994).

    CAS  PubMed  Google Scholar 

  8. 8

    Andoniou, C. E., Thien, C. B. F. & Langdon, W. Y. EMBO J. 13, 4515–4523 (1994).

    CAS  Article  Google Scholar 

  9. 9

    Marcilla, A., Rivero-Lezcano, O. M., Agarwal, A. & Robbins, K. C. J. Biol. Chem. 270, 9115–9120 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Odai, H. et al. J. Biol. Chem. 270, 10800–10805 (1995).

    CAS  Article  Google Scholar 

  11. 11

    Galisteo, M. L., Dikic, I., Batzer, A. G., Langdon, W. Y. & Schlessinger, J. J. Biol. Chem. 270, 20242–20245 (1995).

    CAS  Article  Google Scholar 

  12. 12

    Cory, G. O. C. et al. J. Exp. Med. 182, 611–615 (1995).

    CAS  Article  Google Scholar 

  13. 13

    Wang, Y., Yeung, Y.-G., Langdon, W. Y. & Stanley, E. R. J. Biol. Chem. 271, 17–20 (1996).

    CAS  Article  Google Scholar 

  14. 14

    Schaller, M. D. et al. Proc. Natl Acad. Sci. USA 89, 5192–5196 (1992).

    ADS  CAS  Article  Google Scholar 

  15. 15

    Kamps, M. P. Meth. Enzymol. 201, 21–27 (1991).

    CAS  Article  Google Scholar 

  16. 16

    Blake, T. J., Shapiro, M., Morse III, H. C. & Langdon, W. Y. Oncogene 6, 653–657 (1991).

    CAS  Google Scholar 

  17. 17

    Baron, R., Neff, L., Louvard, D. & Courtoy, P. J. J. Cell Biol. 101, 2010–2022 (1985).

    Article  Google Scholar 

  18. 18

    Baron, R. et al. J. Cell Biol. 106, 1863–1972 (1988).

    CAS  Article  Google Scholar 

  19. 19

    Akatsu, T. et al. J. Bone Miner. Res. 7, 1297–1306 (1992).

    CAS  Article  Google Scholar 

  20. 20

    Weng, Z. et al. Molec. Cell. Biol. 14, 4509–4521 (1994).

    CAS  Article  Google Scholar 

  21. 21

    Peyman, A. & Uhlmann, E. Biol. chem. Hoppe-Seyler 377, 67–70 (1996).

    CAS  Article  Google Scholar 

Download references

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Tanaka, S., Amling, M., Neff, L. et al. c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption. Nature 383, 528–531 (1996). https://doi.org/10.1038/383528a0

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