Cbl family proteins, Cbl and Cbl-b, are E3 ubiquitin ligases and adaptor proteins, which play important roles in bone-resorbing osteoclasts. Loss of Cbl in mice decreases osteoclast migration, resulting in delayed bone development where as absence of Cbl-b decreases bone volume due to hyper-resorptive osteoclasts. A major structural difference between Cbl and Cbl-b is tyrosine 737 (in YEAM motif) only on Cbl, which upon phosphorylation interacts with the p85 subunit of phosphatidylinositol-3 Kinase (PI3K). In contrast to Cbl−/− and Cbl-b−/−, mice lacking Cbl–PI3K interaction due to a Y737F (tyrosine to phenylalanine, YF) mutation showed enhanced osteoclast survival, but defective bone resorption. To investigate whether Cbl–PI3K interaction contributes to distinct roles of Cbl and Cbl-b in osteoclasts, mice bearing CblY737F mutation in the Cbl-b−/− background (YF/YF;Cbl-b−/−) were generated. The differentiation and survival were augmented similarly in YF/YF and YF/YF;Cbl-b−/− osteoclasts, associated with enhanced PI3K signaling suggesting an exclusive role of Cbl–PI3K interaction, independent of Cbl-b. In addition to PI3K, the small GTPase Ras also regulates osteoclast survival. In the absence of Cbl–PI3K interaction, increased Ras GTPase activity and Ras–PI3K binding were observed and inhibition of Ras activation attenuated PI3K mediated osteoclast survival. In contrast to differentiation and survival, increased osteoclast activity observed in Cbl-b−/− mice persisted even after introduction of the resorption-defective YF mutation in YF/YF;Cbl-b−/− mice. Hence, Cbl and Cbl-b play mutually exclusive roles in osteoclasts. Whereas Cbl–PI3K interaction regulates differentiation and survival, bone resorption is predominantly regulated by Cbl-b in osteoclasts. J. Cell. Biochem. 115: 1277–1289, 2014. © 2014 Wiley Periodicals, Inc.
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