Latour S, Zhang J, Siraganian R P, Veillette A
McGill Cancer Centre, McGill University, Montréal, Québec, Canada H3G 1Y6.
EMBO J. 1998 May 1;17(9):2584-95. doi: 10.1093/emboj/17.9.2584.
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 FcepsilonRI 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.
越来越多的数据表明，Syk的“连接区”位于其串联的Src同源2（SH2）结构域和激酶区域之间，对Syk的生物学活性起着关键作用。这种重要性归因于存在能够介导细胞效应器募集的酪氨酸磷酸化位点。我们和其他人之前鉴定出一种Syk的可变剪接变体，称为SykB，它在连接域中缺少一个23个氨基酸的序列。由于这种“连接插入序列”在密切相关的酶Zap-70中也不存在，因此Syk出于功能原因拥有这种独特序列似乎是合理的。为了更好地理解其作用，我们比较了Syk和SykB参与免疫受体触发的信号转导的能力。我们的实验结果表明，与Syk不同，SykB在将嗜碱性粒细胞上的FcepsilonRI或T细胞上的抗原受体的刺激与细胞活化的早期和晚期事件偶联方面效率低下。进一步的研究表明，SykB的功能缺陷不是由关键酪氨酸磷酸化位点的缺失或内在激酶活性的降低引起的。相反，它与SykB在体外和体内结合磷酸化免疫受体酪氨酸基激活基序（ITAM）的能力降低有关。综合这些结果表明，Syk连接域中的独特插入序列对其参与免疫受体信号传导的能力至关重要。此外，它们提供了证据表明连接区可以调节Syk结合ITAM的能力，从而确定了该结构域的一种新功能。
