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A unique insert in the linker domain of Syk is necessary for its function in immunoreceptor signalling

Sylvain Latour, Juan Zhang, Reuben P. Siraganian, André Veillette

Author Affiliations

  1. Sylvain Latour1,
  2. Juan Zhang2,
  3. Reuben P. Siraganian2 and
  4. André Veillette*,3,4,5,6
  1. 1 McGill Cancer Centre, McGill University, Montréal, Québec, Canada, H3G 1Y6
  2. 2 Receptors and Signal Transduction Section, OIIB, NIDR, National Institutes of Health, Bethesda, MD, 20892, USA
  3. 3 Department of Biochemistry, McGill University, Montréal, Québec, Canada, H3G 1Y6
  4. 4 Department of Medicine, McGill University, Montréal, Québec, Canada, H3G 1Y6
  5. 5 Department of Oncology, McGill University, Montréal, Québec, Canada, H3G 1Y6
  6. 6 Department of Medicine and Oncology, Montreal General Hospital, Montréal, Québec, Canada, H3G 1A4
  1. *Corresponding author. E-mail: veillette{at}medcor.mcgill.ca
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Abstract

Accumulating data indicate that the ‘linker’ region of Syk, which lies between its tandem Src homology 2 (SH2) domains and kinase region, provides a critical function for the biological activity of Syk. This importance has been ascribed to the presence of tyrosine phosphorylation sites capable of mediating the recruitment of cellular effectors. We and others previously identified an alternatively spliced variant of Syk, termed SykB, which lacks a 23 amino acid sequence in the linker domain. As this ‘linker insert’ is also not present in the closely related enzyme Zap‐70, it seems plausible that Syk possesses this unique sequence for functional reasons. To understand its role better, we have compared the abilities of Syk and SykB to participate in immunoreceptor‐triggered signal transduction. The results of our experiments revealed that, unlike Syk, SykB was inefficient at coupling stimulation of FcϵRI on basophils or the antigen receptor on T cells to the early and late events of cellular activation. Further studies showed that the functional defect in SykB was not caused by the absence of crucial tyrosine phosphorylation sites, or by a reduced intrinsic kinase activity. Rather, it correlated with the reduced ability of SykB to bind phosphorylated immunoreceptor tyrosine‐based activation motifs (ITAMs) in vitro and in vivo. In combination, these results demonstrated that the unique insert in the linker domain of Syk is crucial for its capacity to participate in immunoreceptor signalling. Furthermore, they provided evidence that the linker region can regulate the ability of Syk to bind ITAMs, thus identifying a novel function for this domain.

  • Received November 17, 1997.
  • Revision received February 23, 1998.
  • Accepted March 11, 1998.
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