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Vol. 20, Issue 18, 4021-4030, September 15, 2009

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c-Cbl and Cbl-b Act Redundantly to Protect Osteoclasts from Apoptosis and to Displace HDAC6 from β-Tubulin, Stabilizing Microtubules and Podosomes

Enkhtsetseg Purev^*, Lynn Neff^*, William C. Horne^*, and Roland Baron^*,,

*Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115; Department of Medicine, Harvard Medical School, Boston, MA 02115; and Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114

Submitted March 26, 2009; Revised June 30, 2009; Accepted July 17, 2009
Monitoring Editor: Richard K. Assoian

c-Cbl and Cbl-b are highly conserved adaptor proteins that participate in integrin signaling, regulating cytoskeletal organization, motility, and bone resorption. Deletion of both c-Cbl and Cbl-b in mice leads to embryonic lethality, indicating that the two proteins perform essential redundant functions. To examine the redundant actions of c-Cbl and Cbl-b in osteoclasts, we depleted c-Cbl in Cbl-b^–/– osteoclasts by using a short hairpin RNA. Depleting both Cbl proteins disrupted both the podosome belt and the microtubule network and decreased bone-resorbing activity. Stabilizing the microtubules with paclitaxel or inhibiting histone deacetylase 6 (HDAC6), which destabilizes microtubules by deacetylating β-tubulin, protected both the microtubule network and the podosome belt. Examination of the mechanism involved demonstrated that the conserved four-helix bundle of c-Cbl's tyrosine kinase binding domain bound to β-tubulin, and both c-Cbl and Cbl-b displaced HDAC6. In addition to the effects on microtubules and the podosome belt, depleting both Cbls significantly increased the levels of the proapoptotic protein Bim and apoptosis relative to the levels induced by eliminating either protein alone. Thus, both c-Cbl and Cbl-b promote bone resorption via the stabilization of microtubules, allowing the formation of the podosome belt in osteoclasts, and by promoting osteoclast survival.

Address correspondence to: Roland Baron (roland_baron{at}hsdm.harvard.edu).

Abbreviations used: OC, osteoclast; OCL, osteoclast-like cell; MT, microtubule.

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