金沙威尼斯欢乐娱人城2016年度秋季学期学术系列讲座之六
题目：Kinase Control in T-cell and B-cell signaling
讲座人：John Kuriyan, PhD
University of California, Berkeley
Howard Hughes Medical Institute
Member of the National Academy of Sciences
Foreign Member of the Royal Society
时间：2016年10月24日，13:00 - 14:30
地点：金沙威尼斯欢乐娱人城邓祐才报告厅
主持人：苏晓东，肖俊宇
摘要：
The activation of B- and T-lymphocytes relies on a chain of tyrosine phosphorylation events initiated by B-cell and T-cell receptors, respectively. These phosphorylation-dependent signals are generated by three kinds of non-receptor tyrosine kinases, linked to the receptor by membrane co-localization. Src-family kinases (e.g, Lck in T-cells), resident at the plasma membrane, respond first to receptor activation. They phosphorylate pairs of tyrosine residues in ITAM motifs in the cytoplasmic tails of activated receptors, which in turn recruit the tandem-SH2 domain tyrosine kinases Syk (in B-cells) and ZAP-70 (in T-cells). Membrane localization of Syk or ZAP-70 leads to the recruitment and activation of Tec-family tyrosine kinases, Btk (in B-cells) and Itk (in T-cells). I will discuss two aspects of these signaling network.

First, using a platform that combines exhaustive point-mutagenesis of peptide substrates, bacterial surface-display, cell sorting, and deep sequencing, we have defined the specificities of the first two kinases in this pathway, Lck and ZAP-70, for the T cell receptor ζ chain and the scaffold proteins LAT and SLP-76. We find that ZAP-70 selects its substrates by utilizing an electrostatic mechanism that excludes substrates with positively-charged residues and favors LAT and SLP-76 phosphosites that are surrounded by negatively-charged residues. This mechanism prevents ZAP-70 from phosphorylating its own activation loop, thereby enforcing its strict dependence on Lck for activation. The sequence features in ZAP-70, LAT, and SLP-76 that underlie electrostatic selectivity likely contribute to the specific response of T cells to foreign antigens.

Second, I will discuss crystallographic and biochemical analyses of Btk, which together reveal molecular details of its autoinhibition and activation. Autoinhibited Btk adopts a compact conformation like that of inactive c-Src and c-Abl. A lipid-binding PH-TH module, unique to Tec kinases, acts in conjunction with the SH2 and SH3 domains to stabilize the inactive conformation. In addition to the expected activation of Btk by membranes containing phosphatidylinositol triphosphate (PIP3), we found that inositol hexakisphosphate (IP6), a soluble signaling molecule found in both animal and plant cells, also activates Btk. This activation is a consequence of a transient PH-TH dimerization induced by IP6, and I will discuss the implications of this mechanism for signaling at the plasma membrane.
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