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CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling


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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  1. Tonks, N. K. & Neel, B. G. From form to function: signaling by protein tyrosine phosphatases. Cell 87, 365–368 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Kishihara, K. et al. Normal B lymphocyte development but impaired T cell maturation in CD45- exon6 protein tyrosine phosphatase-deficient mice. Cell 74, 143–156 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Byth, K. F. et al. CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation. J. Exp. Med. 183, 1707–1718 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Trowbridge, I. S. & Thomas, M. L. CD45: an emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development. Annu. Rev. Immunol. 12, 85–116 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. Thomas, M. L. The leukocyte common antigen family. Annu. Rev. Immunol. 7, 339–369 (1989).

    Article  CAS  PubMed  Google Scholar 

  6. de Groot, R. P., Coffer, P. J. & Koenderman, L. Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family. Cell Signal. 10, 619–628 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Leonard, W. J. & O'Shea, J. J. Jaks and STATs: biological implications. Annu. Rev. Immunol. 16, 293– 322 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Matsumura, I. et al. Transcriptional regulation of the cyclin D1 promoter by STAT5: its involvement in cytokine-dependent growth of hematopoietic cells. EMBO J. 18, 1367–1377 ( 1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hanke, J. H. et al. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J. Biol. Chem. 271, 695–701 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Felberg, J. & Johnson, P. Characterization of recombinant CD45 cytoplasmic domain proteins. Evidence for intramolecular and intermolecular interactions. J. Biol. Chem. 273, 17839– 17845 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. McKenney, D. W., Onodera, H., Gorman, L., Mimura, T. & Rothstein, D. M. Distinct isoforms of the CD45 protein-tyrosine phosphatase differentially regulate interleukin 2 secretion and activation signal pathways involving Vav in T cells. J. Biol. Chem. 270, 24949–24954 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Ihle, J. N. Cytokine receptor signalling. Nature 377, 591–594 (1995).

    Article  CAS  ADS  PubMed  Google Scholar 

  13. Petricoin, E. F. I. et al. Antiproliferative action of interferon-α requires components of T-cell-receptor signalling. Nature 390, 629–632 (1997).

    Article  CAS  ADS  PubMed  Google Scholar 

  14. Parganas, E. et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell 93, 385– 395 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Marine, J. C. et al. SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell 98, 617–627 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Rodig, S. J. et al. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 93, 373–383 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  17. Kandolf, R., Canu, A. & Hofschneider, P. H. Coxsackie B3 virus can replicate in cultured human foetal heart cells and is inhibited by interferon. J. Mol. Cell. Cardiol. 17, 167–181 ( 1985).

    Article  CAS  PubMed  Google Scholar 

  18. Ward, A. C., Touw, I. & Yoshimura, A. The Jak–Stat pathway in normal and perturbed hematopoiesis. Blood 95, 19–29 (2000).

    CAS  PubMed  Google Scholar 

  19. Yasukawa, H. et al. The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J. 18, 1309–1320 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Klingmüller, U., Lorenz, U., Cantley, L. C., Neel, B. G. & Lodish, H. F. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 80, 729– 738 (1995).

    Article  PubMed  Google Scholar 

  21. Ratei, R. et al. Immunophenotype and clinical characteristics of CD45-negative and CD45-positive childhood acute lymphoblastic leukemia. Ann. Hematol. 77, 107–114 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  22. Ozdemirli, M., Mankin, H. J., Aiesenberg, A. C. & Harris, N. L. Hodgkin's disease presenting as a solitary bone tumor. A report of four cases and review of the literature. Cancer 77, 79–88 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Kung, C. et al. Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nature Medicine 6, 343–345 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Saad, M. J., Carvalho, C. R., Thirone, A. C. & Velloso, L. A. Insulin induces tyrosine phosphorylation of JAK2 in insulin-sensitive tissues of the intact rat. J. Biol. Chem. 271, 22100 –22104 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Ren, J. M. et al. Transgenic mice deficient in the LAR protein-tyrosine phosphatase exhibit profound defects in glucose homeostasis. Diabetes 47, 493–497 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Liu, Q. et al. SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival. Genes Dev. 13, 786–791 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chaturvedi, P., Sharma, S. & Reddy, E. P. Abrogation of interleukin-3 dependence of myeloid cells by the v-src oncogene requires SH2 and SH3 domains which specify activation of STATs. Mol. Cell. Biol. 17, 3295– 3304 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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).

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