Evolution of Antigen Receptor Signaling

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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.