CEK8--A NOVEL NEURAL RECEPTOR TYROSINE KINASE

Cek8是新近发现的一种受体类型 Eph亚类的酪氨酸激酶，它优先在 神经组织。Cek8的胞外区含有基序 细胞黏附分子的特征，而细胞质结构域 包括一个典型的酪氨酸激酶催化结构域。初步数据 提示Cek8及其哺乳动物同源物可能具有调节功能 神经系统发育中的细胞相互作用和轴突生长。 此外，CEK8可能与卵巢癌的形成有关。 神经系统。拟议研究的目标是提供 用多种不同的方法洞察CEK8的神经功能 分子方法。Cek8的细胞和亚细胞定位 胚胎发育中的神经系统和分离的神经 文化将被详细研究，与发展的 Cek8体内催化活性的调节和水平。例如, CEK8可能集中在生长锥体和 将探讨与轴突引导有关的问题。这些研究将提供 关于CEK8功能的初步线索。黄曲霉的分子组成 Cek8参与的信号通路将被解剖 研究CEK8与具有相似结构的分子的相互作用 神经系统的定位。神经元黏附分子， 蛋白多糖和细胞质酪氨酸激酶是已知的 可能参与与CEK8功能相互作用的分子。其他 与CEK8相互作用的分子，如S配体或底物，也将是 根据它们与CEK8结合的能力进行搜索。最后， Cek8的表达和活性将受到抗体的干扰，a Cek8、Cek8反义序列和IF的显性否定形式 已确定，CEK8激活了木质素。这些研究将在 在体内和体外直接解决CEK8的功能，特别是 在轴突生长过程中。CEK8及其分子的表征 与之相互作用，这将在拟议的研究中解决， 将提供操纵神经信号所需的信息 Cek8参与的信号转导通路。因此，这些研究 很可能成为开发治疗方法的基础 改善特定发育神经病理和退行性变 神经系统疾病。

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.