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Feedback inhibition of calcineurin and Ras by a dual inhibitory protein Carabin

Nature volume 445, pages 433–436 (2007)Cite this article

Abstract

Feedback regulation of adaptive immunity is a fundamental mechanism for controlling the overall output of different signal transduction pathways, including that mediated by the T-cell antigen receptor (TCR)1. Calcineurin2,3,4 and Ras5,6,7 are known to have essential functions during T-cell activation. However, how the calcineurin signalling pathway is terminated in the process is still largely unknown. Although several endogenous inhibitors of calcineurin have been reported8,9,10,11,12,13, none fulfils the criteria of a feedback inhibitor, as their expression is not responsive to TCR signalling. Here we identify an endogenous inhibitor of calcineurin, named Carabin, which also inhibits the Ras signalling pathway through its intrinsic Ras GTPase-activating protein (GAP) activity. Expression of Carabin is upregulated on TCR signalling in a manner that is sensitive to inhibitors of calcineurin, indicating that Carabin constitutes part of a negative regulatory loop for the intracellular TCR signalling pathway. Knockdown of Carabin by short interfering RNA led to a significant enhancement of interleukin-2 production by antigen-specific T cells in vitro and in vivo. Thus, Carabin is a negative feedback inhibitor of the calcineurin signalling pathway that also mediates crosstalk between calcineurin and Ras.

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Figure 1: Carabin interacts with calcineurin in vitro and in vivo.
Figure 2: Carabin inhibits calcineurin activity in vitro and in vivo.
Figure 3: Carabin possesses Ras GAP activity and decreases ERK1/2 phosphorylation on T-cell activation.
Figure 4: Carabin expression is inducible in primary human CD4 + T cells, and knockdown of Carabin causes upregulation of IL-2 production.

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Acknowledgements

We thank members of the Liu laboratory, H. Yu and G. Zhou for helpful discussions, and F. McKeon, A. Rao and D. Shalloway for plasmids. This work was supported by funds from the Department of Pharmacology, Johns Hopkins School of Medicine and the Keck Foundation.

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Author notes

  1. Luo Sun

    Present address: New England Biolabs, Inc., Ipswich, Massachusetts, 01938, USA

Authors and Affiliations

  1. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA

    Fan Pan, Luo Sun & Jun O. Liu

  2. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA

    Jun O. Liu

  3. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA

    Jun O. Liu

  4. Immunology and Hematopoiesis Division, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21231, USA

    David B. Kardian, Katharine A. Whartenby & Drew M. Pardoll

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  1. Fan Pan
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Correspondence to Jun O. Liu.

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Pan, F., Sun, L., Kardian, D. et al. Feedback inhibition of calcineurin and Ras by a dual inhibitory protein Carabin. Nature 445, 433–436 (2007). https://doi.org/10.1038/nature05476

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