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CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling

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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Figure 1: CD45 negatively regulates cytokine-induced activation of mast cells and JAKs.
Figure 2: CD45 deficiency leads to increased tyrosine phosphorylation of STATs.
Figure 3: CD45 dephosphorylates JAKs in vitro.
Figure 4: JAKs are hyperphosphorylated in CD45-deficient B cells, thymocytes and Jurkat T cells.
Figure 5: Enhanced erythroid colony formation and antiviral activity in the absence of CD45.

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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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Correspondence to Takehiko Sasaki.

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Irie-Sasaki, J., Sasaki, T., Matsumoto, W. et al. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409, 349–354 (2001). https://doi.org/10.1038/35053086

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