Cek8 (Chicken embryo kinase 8) is a recently identified receptor-type tyrosine kinase of the Eph subclass which is preferentially expressed in neural tissues. The extracellular domain of Cek8 contains motifs characteristic of cell adhesion molecules, while the cytoplasmic domain comprises a typical tyrosine kinase catalytic domain. Preliminary data indicate that Cek8 and its mammalian homologs may function to regulate cellular interactions and axonal growth in the developing nervous system. Furthermore, Cek8 may be implicated in the formation of tumors of the nervous system. The objectives of the proposed research are to provide insight into the neural functions of Cek8 by using a variety of different molecular approaches. The cellular and subcellular localization of Cek8 in the nervous system of the developing embryo and in dissociated neural cultures will be studied in detail, together with the developmental regulation and level of catalytic activation of Cek8 in vivo. For example, the possibility that Cek8 may be concentrated in growth cones and implicated in axonal guidance will be explored. These studies will provide the initial clues about the functions of Cek8. The molecular components of the signaling pathways in which Cek8 is implicated will be dissected by investigating the interactions of Cek8 with molecules that have a similar localization in the nervous system. Neuronal adhesion molecules, proteoglycans and cytoplasmic tyrosine kinases are among the known molecules that may participate in functional interactions with Cek8. Other molecules interacting with Cek8, such s ligands or substrates, will also be searched for based on their ability to bind to Cek8. Finally, the expression and activity of Cek8 will be perturbed with antibodies, a dominant negative form of Cek8, Cek8 antisense sequences and, if identified, the Cek8 activating lignad. These studies will be performed in vivo and in vitro to address directly the functions of Cek8, particularly during axonal growth. The characterization of Cek8 and of the molecules that interact with it, which will be addressed in the proposed studies, will provide the information necessary to manipulate the neural signal transduction pathways in which Cek8 is implicated. Thus, the studies proposed are likely to form the basis for the development of treatments to ameliorte specific developmental neural pathologies and degenerative diseases of the nervous system.
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