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Proteolysis-independent regulation of PI3K by Cbl-b–mediated ubiquitination in T cells

Nature Immunology volume 2, pages 870–875 (2001)Cite this article

Abstract

Cbl-b, a ring-type E3 ubiquitin protein ligase, is implicated in setting the threshold of T lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (PI3K) was identified as a substrate for Cbl-b. We have shown that Cbl-b negatively regulated p85 in a proteolysis-independent manner. Cbl-b is involved in the recruitment of p85 to CD28 and T cell antigen receptor ζ through its E3 ubiquitin ligase activity. The enhanced activation of Cbl-b−/− T cells was suppressed by the inhibition of PI3K. The results suggest a proteolysis-independent function for Cbl-b in the modification of protein recruitment.

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Figure 1: Cbl-b does not affect the stability of p85.
Figure 2: Cbl-b regulates p85 recruitment to CD28.
Figure 3: A functional role for the Cbl-b ring finger.
Figure 4: Effect of PI3K inhibitors on T cell activation.
Figure 5: Cbl-b deficiency affects the association between p85 and TCRζ.
Figure 6: Effect of CD28 deficiency on PI3K activation.

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Acknowledgements

We thank C. Elly, B. Gao and Y. Altman for technical assistance; A. Altman and members of the Division of Cell Biology for support and suggestions; M. Naramura and H. Gu for Cbl-b−/− mice; and J. Penninger for discussions. Supported by National Institutes of Health Grant RO1DK56558 and arthritis foundation (Y.-C. L.).

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  1. Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, 92121, CA, USA

    Deyu Fang & Yun-Cai Liu

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Correspondence to Yun-Cai Liu.

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Fang, D., Liu, YC. Proteolysis-independent regulation of PI3K by Cbl-b–mediated ubiquitination in T cells. Nat Immunol 2, 870–875 (2001). https://doi.org/10.1038/ni0901-870

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