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LYP inhibits T-cell activation when dissociated from CSK

Nature Chemical Biology volume 8, pages 437–446 (2012)Cite this article

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Abstract

Lymphoid tyrosine phosphatase (LYP) and C-terminal Src kinase (CSK) are negative regulators of signaling mediated through the T-cell antigen receptor (TCR) and are thought to act in a cooperative manner when forming a complex. Here we studied the spatiotemporal dynamics of the LYP–CSK complex in T cells. We demonstrate that dissociation of this complex is necessary for recruitment of LYP to the plasma membrane, where it downmodulates TCR signaling. Development of a potent and selective chemical probe of LYP confirmed that LYP inhibits T-cell activation when removed from CSK. Our findings may explain the reduced TCR-mediated signaling associated with a single-nucleotide polymorphism that confers increased risk for certain autoimmune diseases, including type 1 diabetes and rheumatoid arthritis, and results in expression of a mutant LYP that is unable to bind CSK. Our compound also represents a starting point for the development of a LYP-based treatment of autoimmunity.

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Figure 1: LYP recruited to lipid rafts downmodulates TCR-signaling independently of CSK.
Figure 2: High-throughput screening and counterscreens for LYP inhibitors.
Figure 3: LTV-1 is a potent LYP inhibitor in T cells.
Figure 4: LTV-1 binds the LYP active site in open conformation.
Figure 5: LTV-1 specifically inhibits LYP in T cells.
Figure 6: LYP downmodulates TCR signaling when dissociated from CSK.
Figure 7: Proposed model of how LYP and CSK control TCR-induced signaling.

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  • 30 March 2012

    In the version of this article initially published online, the C1858 allele of PTPN22 was inadvertently referred to as the Cys1858 allele in the results section "Effects of LTV-1 on TCR signaling in primary human T cells". The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank L. Smith and the Exploratory Pharmacology Core at Sanford-Burnham Medical Research Institute for support and thoughtful discussions; S. Ormenese and the Groupe Interdisciplinaire de Génoprotéomique Appliquée Imaging Core for their help with flow cytometry; and G.M. Tjørhom, S.T. Flåm and J. Solheim for technical assistance. This work was supported by the US National Institutes of Health (grant 1R21CA132121 to L.T.), the Norwegian Cancer Society (T.V.), the American Cancer Society (research scholar grant RSG-08-067-01-LIB to R.P.), the Oxnard Foundation (research grant to T.M./R.C.R.), the Belgian Research National Scientific Fund (Mandat d'Impulsion Scientifique Young Investigator Starting Grant to S.R.) and the Liège University (startup grant to S.R.).

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Author notes

  1. Tomas Mustelin

    Present address: Current address: MedImmune LLC, Gaithersburg, Maryland, USA.,

  2. Wallace H Liu and Laurence Delacroix: These authors contributed equally to this work.

Authors and Affiliations

  1. Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA

    Torkel Vang, Wallace H Liu, Shuangding Wu, Tomas Mustelin, Robert C Rickert & Lutz Tautz

  2. The Biotechnology Center of Oslo, University of Oslo, Oslo, Norway

    Torkel Vang, Johannes Landskron & Kjetil Tasken

  3. Immunology and Infectious Diseases Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée–Signal Transduction, Liège University, Liège, Belgium

    Laurence Delacroix, Lucia Musumeci & Souad Rahmouni

  4. Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, La Jolla, California, USA

    Stefan Vasile, Russell Dahl & Li Yang

  5. Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA

    Dana Francis & Rebecca Page

  6. Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada

    Michel L Tremblay

  7. Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway

    Benedicte A Lie

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Contributions

T.V., W.H.L., L.D., S.W., R.D., B.A.L., S.R. and L.T. designed research, performed research, analyzed data and wrote the paper; S.V., L.Y., L.M., D.F. and J.L. designed research, performed research and analyzed data; K.T. and M.L.T. contributed new reagents or analytical tools; R.P. designed research, analyzed data and wrote the paper; and T.M. and R.C.R. designed research.

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Correspondence to Lutz Tautz.

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Vang, T., Liu, W., Delacroix, L. et al. LYP inhibits T-cell activation when dissociated from CSK. Nat Chem Biol 8, 437–446 (2012). https://doi.org/10.1038/nchembio.916

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