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Abstract

The regulation of tyrosine phosphorylation and associated signalling through antigen, growth-factor and cytokine receptors is mediated by the reciprocal activities of protein tyrosine kinases and protein tyrosine phosphatases (PTPases)1. The transmembrane PTPase CD45 is a key regulator of antigen receptor signalling in T and B cells2,3. Src-family kinases have been identified as primary molecular targets for CD45 (ref. 4). However, CD45 is highly expressed in all haematopoietic lineages at all stages of development5, indicating that CD45 could regulate other cell types and might act on additional substrates. Here we show that CD45 suppresses JAK (Janus kinase) kinases and negatively regulates cytokine receptor signalling. Targeted disruption of the cd45 gene leads to enhanced cytokine and interferon-receptor-mediated activation of JAKs and STAT (signal transducer and activators of transcription) proteins. In vitro , CD45 directly dephosphorylates and binds to JAKs. Functionally, CD45 negatively regulates interleukin-3-mediated cellular proliferation, erythropoietin-dependent haematopoieisis and antiviral responses in vitro and in vivo. Our data identify an unexpected and novel function for CD45 as a haematopoietic JAK phosphatase that negatively regulates cytokine receptor signalling.

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Acknowledgements

We thank M. Saunders for scientific editing; T. Mak for providing CD45 mutant mice; and T. Mak, M. Reth, W. Yeh, D. Barber, V. Stambolic, C. Mirtsos, K. Bachmaier, A. Oliveira-dos-Santos, M. Crackower, Y. Kong, N. Joza, I. Kozieradzki and Q. Liu for comments and advice. This work was supported by grants from the Canadian Institutes for Health Research (CIHR) and the National Cancer Institute (NCI) of Canada and Amgen to J.M.P., and from the NIH to D.M.R. J.M.P. holds a Canadian Research Chair in Cell Biology.

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Author notes

    • Junko Irie-Sasaki
    •  & Takehiko Sasaki

    These authors contributed equally to this work

    • Junko Irie-Sasaki
    •  & Takehiko Sasaki

    Present address: Department of Pharmacology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome , Bunkyo-ku, Tokyo, Japan 113-8613 .

Affiliations

  1. *Amgen Institute, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, University of Toronto, 620 University Avenue, Toronto, Ontario M5G 2C1, Canada

    • Junko Irie-Sasaki
    • , Takehiko Sasaki
    • , Mary Cheng
    • , Grant Welstead
    • , Emily Griffiths
    • , Connie Krawczyk
    • , Christopher D. Richardson
    •  & Josef M. Penninger
  2. §Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06529-8029, USA

    • Wataru Matsumoto
    •  & David M. Rothstein
  3. Heart and Stroke/Lewar Centre of Excellence in Cariovascular Research, University Health Network, University of Toronto, 200 Elizabeth Street, M5G 2C4, Canada

    • Anne Opavsky
    • , Karen Aitken
    • , Peter Liu
    •  & Josef M. Penninger
  4. ¶Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada

    • Norman Iscove
  5. #Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 421 Cukic Boulevard, Philadelphia, Pennsylvania 19104, USA

    • Gary Koretzky
  6. Departments of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

    • Pauline Johnson

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Correspondence to Takehiko Sasaki.

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https://doi.org/10.1038/35053086

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