Wnt signaling via the Drl axon guidance receptor

描述（由申请人提供）：生长中的神经元必须通过感知调节细胞运动的引导线索来识别并遵循特定的通路到达其突触靶点。在果蝇中，Drl受体由神经元的子集表达，并且是适当的轴突寻路所需的。Drl是非典型受体酪氨酸激酶（RTK）的Ryk家族的成员，其是Wnt配体的催化失活受体。Wnt配体通常在不同于RTK的信号传导途径中起作用，其参与多种疾病过程，如癌细胞侵袭和转移。人类Drl直系同源物Ryk也与许多癌症有关。然而，关于Ryk家族受体响应于Wnt而启动的信号传导事件知之甚少。该提议的更广泛的目标是鉴定和表征Drl和Wnt蛋白用于调节细胞运动的信号传导途径。将使用蛋白质组学、细胞生物学和遗传学方法阐明Drl信号传导活性，以1）分析Drl胞质结构域的功能区域，2）研究Drl膜内蛋白水解的作用和释放的Drl胞质结构域的功能，3）鉴定Drl结合蛋白，和4）表征Drl结合蛋白和候选Drl信号传导效应物。

DESCRIPTION (provided by applicant): Growing neurons must recognize and follow specific pathways to their synaptic targets by sensing guidance cues that regulate cell motility. In Drosophila, the Drl receptor is expressed by a subset of neurons and is required for proper axon pathfinding. Drl is a member of the Ryk family of atypical receptor tyrosine kinases (RTKs), which are catalytically inactive receptors for Wnt ligands. Wnt ligands, which typically function in signaling pathways distinct from RTKs, are involved in multiple disease processes such as cancer cell nvasiveness and metastasis. The human Drl ortholog, Ryk, has also been implicated in numerous cancers. Yet, little is known about the signaling events initiated by Ryk family receptors in response to Wnts. The broader goal of this proposal is to identify and characterize the signaling pathways employed by Drl and Wnt proteins to regulate cell motility. Drl signaling activity will be elucidated using proteomic, cell-biological, and genetic approaches to 1) Analyze the Drl cytoplasmic domain for functional regions, 2) Investigate the role Drl ntramembrane proteolysis and the function of the released Drl cytoplasmic domain, 3) Identify Drl binding proteins, and 4) Characterize Drl-binding proteins and candidate Drl signaling effectors.