SHARK KINASE SIGNALING IN THE ECOTDERMAL EPITHELIUM

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We have recently identified a non-receptor tyrosine kinase that, during Drosophila embryogenesis, is exclusively expressed by the ectodermally derived epithelia and is preferentially localized to the apical epithelial surface. It contains, from amino terminus to carboxy terminus, a Src homology (SH2) domain, 5 ankyrin repeats, another SH2 domain, a proline-rich and basic region and a tyrosine kinase domain. We have termed this kinase Shark (SH2 domain ankyrin repeat kinase). The Shark structure and localization pattern suggest that it functions in a signaling pathway for epithelial cell polarity and/or fate of the ectodermally derived epithelium. We propose to: 1. Determine the loss-of-function and gain-of-function phenotypes of shark. 2. Identify proteins that physically interact with Shark. 3. Investigate the role of the functional domains of Shark. 4. Identify and characterize genes interacting with shark. 5. Identify the mouse homologue(s) of Shark. We wish to use these approaches to investigate the action of Shark and identify other components of the signaling pathway(s) in which it functions. Shark is a novel tyrosine kinase that, apart from its kinase domain, contains three different types of domains known to be important in protein-protein interactions in signal transduction. As both tyrosine kinases and ankyrin repeats have been shown to transduce developmental signals and SH2 domains are involved in tyrosine kinase signaling, Shark could lie at an intersection between ankyrin repeat and tyrosine kinase pathways. A Hydra homologue of Shark, HTK16, also expressed in epithelium, has been reported and preliminary data indicate the existence a human homologue(s) suggesting that Shark is involved in regulating fundamental processes in metazoans. Elucidation of the pathways in which Shark functions is therefore expected to yield new information about the development, regulation and maintenance of epithelium.