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Syk tyrosine kinase required for mouse viability and B-cell development

Nature volume 378, pages 303306 (16 November 1995) | Download Citation

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Abstract

THE Syk cytoplasmic protein-tyrosine kinase has two amino-terminal SH2 domains and a carboxy-terminal catalytic domain1. Syk, and its close relative ZAP-70 (ref. 2), are apparently pivotal in coupling antigen- and Fc-receptors to downstream signalling events3,4. Syk associates with activated Fc receptors5, the T cell receptor complex6 and the B-cell antigen-receptor complex (BCR) in immature and mature B lymphocytes7. On receptor activation, the tandem SH2 domains of Syk bind dual phosphotyrosine sites in the conserved ITAM motifs of receptor signalling chains, such as the immunoglobulin α and β-chains of the BCR, leading to Syk activation3,4,8. Here we have investigated Syk function in vivo by generating a mouse strain with a targeted mutation in the syk gene. Homozygous syk mutants suffered severe haemorrhaging as embryos and died perinatally, indicating that Syk has a critical role in maintaining vascular integrity or in wound healing during embryogenesis. Analysis of syk−/− lymphoid cells showed that the syk mutation impaired the differentiation of B-lineage cells, apparently by disrupting signalling from the pre-BCR complex and thereby preventing the clonal expansion, and further maturation, of pre-B cells.

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Affiliations

  1. Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave, Toronto, Ontario M5G 1X5, Canada

    • Alec M. Cheng
    •  & Tony Pawson
  2. Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08453, USA

    • Bruce Rowley
    •  & Joseph B. Bolen
  3. Department of Biology, Yale University, KBT 616, PO Box 208103, New Haven, Connecticut 06520-8103, USA

    • William Pao
    •  & Adrian Hayday
  4. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada

    • Tony Pawson

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https://doi.org/10.1038/378303a0

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