Evolution of Antigen Receptor Signaling

多细胞动物进化过程中的一个关键创新是区分自我与非自我的能力。在脊椎动物中，这种识别的分子机制已经得到了相当详细的了解，特别是在各种抗原受体介导的情况下。然而，尽管付出了相当大的努力，仍不可能将脊椎动物抗原受体的进化史追溯到任何早于有颌鱼类分化的后生动物分类群。这些努力一直集中在利用分子方法试图识别编码脊椎动物抗原受体同源物的基因。该项目将利用一种不同的方法来解决抗原受体信号的起源，该方法基于对Syk家族蛋白酪氨酸激酶（PTK）的早期分化无脊椎水螅的发现。Syk PTKs通过两个src同源2结构域与脊椎动物抗原受体细胞质尾部磷酸化酪氨酸残基相互作用。因此，与Hydra Syk相互作用的分子是介导该生物体中外来细胞识别的候选分子，并且可能与脊椎动物抗原受体进化相关。该项目的目的是确定与Hydra Syk相互作用的分子，从而追踪抗原受体信号通路的进化史。初步实验将测试Hydra Syk与脊椎动物抗原受体的结合能力和功能。在这种情况下，一个积极的结果将为在广泛的后生动物进化中保持Syk/受体相互作用的基本机制提供支持。随后的实验将致力于确定Syk在Hydra中与之相互作用的分子。将这些分子与脊椎动物蛋白质进行比较，可以表明它们与脊椎动物抗原受体之间是否存在进化连续性。如果这种连续性不明显，九头蛇中相互作用蛋白与其他后生动物蛋白的关系仍将揭示重要的、目前无法获得的、关于信号通路进化史的信息，这些信号通路被修改用于脊椎动物抗原受体。

A key innovation during the evolution of multicellular animals was the ability to distinguish self from non-self. The molecular mechanisms underlying such recognition are understood in considerable detail in vertebrates, particularly as mediated by the various classes of antigen receptors. Despite considerable effort, however, it has not been possible to trace the evolutionary history of vertebrate antigen receptors into any metazoan taxon which diverged earlier than the jawed fishes. Such efforts have been focused on the use of molecular methods in attempts to identify genes encoding orthologues of vertebrate antigen receptors. This project will makes use of a different approach to address the origins of antigen receptor signaling, based on the finding in the early-diverging invertebrate Hydra of a Syk family protein-tyrosine kinase (PTK). Syk PTKs interact with phosphorylated tyrosine residues on the cytoplasmic tails of antigen receptors in vertebrates through two src homology 2 domains. Thus the molecules with which Hydra Syk interacts are candidates for mediating recognition of foreign cells in this organism, and are potentially evolutionarily related to vertebrate antigen receptors. The objective of this project is to identify the molecules with which Hydra Syk interacts and thereby to trace the evolutionary history of the antigen receptor signaling pathway. Initial experiments will test the ability of Hydra Syk to bind to and function with vertebrate antigen receptors. A positive result in this case would provide support for conservation of the basic mechanics of Syk/receptor interaction over a wide range of metazoan evolution. Subsequent experiments will be directed towards identifying the molecules with which Syk interacts in Hydra. Comparisons of these molecules with vertebrate proteins should indicate whether there is any evolutionary continuity between them and vertebrate antigen receptors. If no such continuity is evident, the relationships of the interacting proteins in Hydra with the proteins of other metazoans will nonetheless reveal important, and currently unavailable, information regarding the evolutionary history of the signaling pathway which was modified for use with vertebrate antigen receptors.