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CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling

Author

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  • Junko Irie-Sasaki

    (Amgen Institute, Ontario Cancer Institute, University of Toronto
    Tokyo Metropolitan Institute of Medical Science)

  • Takehiko Sasaki

    (Amgen Institute, Ontario Cancer Institute, University of Toronto
    Tokyo Metropolitan Institute of Medical Science)

  • Wataru Matsumoto

    (Department of Internal Medicine Yale University School of Medicine)

  • Anne Opavsky

    (Heart and Stroke/Lewar Centre of Excellence in Cariovascular Research, University Health Network, University of Toronto)

  • Mary Cheng

    (Amgen Institute, Ontario Cancer Institute, University of Toronto)

  • Grant Welstead

    (Amgen Institute, Ontario Cancer Institute, University of Toronto)

  • Emily Griffiths

    (Amgen Institute, Ontario Cancer Institute, University of Toronto)

  • Connie Krawczyk

    (Amgen Institute, Ontario Cancer Institute, University of Toronto)

  • Christopher D. Richardson

    (Amgen Institute, Ontario Cancer Institute, University of Toronto)

  • Karen Aitken

    (Heart and Stroke/Lewar Centre of Excellence in Cariovascular Research, University Health Network, University of Toronto)

  • Norman Iscove

    (Ontario Cancer Institute)

  • Gary Koretzky

    (University of Pennsylvania School of Medicine)

  • Pauline Johnson

    (Departments of Microbiology and Immunology University of British Columbia)

  • Peter Liu

    (Heart and Stroke/Lewar Centre of Excellence in Cariovascular Research, University Health Network, University of Toronto)

  • David M. Rothstein

    (Department of Internal Medicine Yale University School of Medicine)

  • Josef M. Penninger

    (Amgen Institute, Ontario Cancer Institute, University of Toronto
    Heart and Stroke/Lewar Centre of Excellence in Cariovascular Research, University Health Network, University of Toronto)

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.

Suggested Citation

  • Junko Irie-Sasaki & Takehiko Sasaki & Wataru Matsumoto & Anne Opavsky & Mary Cheng & Grant Welstead & Emily Griffiths & Connie Krawczyk & Christopher D. Richardson & Karen Aitken & Norman Iscove & Gar, 2001. "CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling," Nature, Nature, vol. 409(6818), pages 349-354, January.
    • Handle: RePEc:nat:nature:v:409:y:2001:i:6818:d:10.1038_35053086
    DOI: 10.1038/35053086
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    Cited by:

    1. Jongho Ham & Jihyun Kim & Kyoung-Hee Sohn & In-Won Park & Byoung-Whui Choi & Doo Hyun Chung & Sang-Heon Cho & Hye Ryun Kang & Jae-Woo Jung & Hye Young Kim, 2022. "Cigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Gaurav Dwivedi & Margaret A Gran & Pritha Bagchi & Melissa L Kemp, 2015. "Dynamic Redox Regulation of IL-4 Signaling," PLOS Computational Biology, Public Library of Science, vol. 11(11), pages 1-20, November.

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