Departamento de Bioquimíca, Biología Molecular B e Inmunología, Facultad de Medicina, Universidad de Murcia, Murcia, Spain.
J Leukoc Biol. 2011 Jan;89(1):63-73. doi: 10.1189/jlb.0509342. Epub 2010 Oct 12.
The adaptor protein LAT has a prominent role in the transduction of intracellular signals elicited by the TCR/CD3 complex. Upon TCR engagement, LAT becomes tyrosine-phosphorylated and thereby, recruits to the membrane several proteins implicated in the activation of downstream signaling pathways. However, little is known about the role of other conserved motifs present in the LAT sequence. Here, we report that the adaptor LAT contains several conserved serine-based motifs, which are essential for proper signal transduction through the TCR. Mutation of these serine motifs in the human T cell line Jurkat prevents proper calcium influx, MAPK activation, and IL-2 production in response to TCR/CD3 stimulation. Moreover, this mutant form of LAT has a reduced ability to bind to PLC-γ1 and SLP-76, although phosphorylation of tyrosine residues 132, 171, and 191 is not decreased, raising a possible role for the serine-based motifs of LAT for the binding of important partners. The functional role of LAT serine-based motifs in signal transduction could be mediated by an effect on tyrosine phosphorylation, as their mutation significantly diminishes the phosphorylation of tyrosine residue 226. In addition, these serine motifs seem to have a regulatory role, given that upon their mutation, ZAP-70 shows enhanced phosphorylation. Therefore, the LAT serine-based motifs likely regulate signaling pathways that are essential for T cell physiology.
衔接蛋白 LAT 在 T 细胞受体/CD3 复合物引发的细胞内信号转导中起着重要作用。TCR 结合后，LAT 发生酪氨酸磷酸化，从而募集几种与下游信号通路激活有关的蛋白到膜上。然而，关于 LAT 序列中其他保守基序的作用知之甚少。在这里，我们报告衔接蛋白 LAT 包含几个保守的丝氨酸基序，这些基序对于通过 TCR 进行适当的信号转导是必不可少的。在人类 T 细胞系 Jurkat 中突变这些丝氨酸基序可阻止钙内流、MAPK 激活和 IL-2 的产生对 TCR/CD3 刺激的反应。此外，这种 LAT 的突变形式与 PLC-γ1 和 SLP-76 的结合能力降低，尽管酪氨酸残基 132、171 和 191 的磷酸化没有减少，这表明 LAT 的丝氨酸基序可能对重要伴侣的结合具有潜在作用。LAT 丝氨酸基序在信号转导中的功能作用可能通过对酪氨酸磷酸化的影响来介导，因为它们的突变显著降低了酪氨酸残基 226 的磷酸化。此外，这些丝氨酸基序似乎具有调节作用，因为在它们突变后，ZAP-70 的磷酸化增强。因此，LAT 丝氨酸基序可能调节对 T 细胞生理学至关重要的信号通路。
