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和非自我的能力。这种识别的分子机制在脊椎动物中有相当详细的了解，特别是由各种类型的抗原受体介导的。然而，尽管付出了相当大的努力，仍然不可能将脊椎动物抗原受体的进化历史追溯到比有颌鱼类更早分化的任何后生动物分类群。这些努力集中于使用分子方法来尝试鉴定编码脊椎动物抗原受体直向同源物的基因。该项目将利用一种不同的方法来解决抗原受体信号传导的起源，基于在早期分化的无脊椎动物水螅中发现的Syk家族蛋白酪氨酸激酶（PTK）。Syk PTK通过两个src同源2结构域与脊椎动物中抗原受体胞质尾部上的磷酸化酪氨酸残基相互作用。因此，与水螅Syk相互作用的分子是介导这种生物体中外来细胞识别的候选者，并且在进化上与脊椎动物抗原受体潜在相关。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历史。最初的实验将测试Hydra Syk与脊椎动物抗原受体结合并发挥作用的能力。在这种情况下，一个积极的结果将提供支持的Syk/受体相互作用的基本机制在广泛的后生动物进化的保护。随后的实验将针对确定与Syk在Hydra中相互作用的分子。这些分子与脊椎动物蛋白质的比较应该表明它们与脊椎动物抗原受体之间是否存在任何进化连续性。如果没有这样的连续性是明显的，在水螅与其他后生动物的蛋白质的相互作用的蛋白质的关系将仍然揭示重要的，目前不可用的，信息有关的进化历史的信号通路被修改用于与脊椎动物抗原受体。

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.