Wnt signaling via the Drl axon guidance receptor

描述(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指导信号来识别并遵循特定的路径到达它们的突触目标。在果蝇中，DRL受体由一小部分神经元表达，是正确寻找轴突路径所必需的。DRL是非典型受体酪氨酸激酶(RTKs)Ryk家族的成员，RTKs是Wnt配体的催化失活受体。WNT配体通常在不同于RTK的信号通路中发挥作用，参与多种疾病过程，如癌细胞侵袭和转移。人类DRL同源基因Ryk也与许多癌症有关。然而，关于Ryk家族受体对Wnts的反应所引发的信号事件知之甚少。这项提议的更广泛的目标是识别和表征DRL和WNT蛋白用来调节细胞运动的信号通路。DRL信号活性将通过蛋白质组学、细胞生物学和遗传学方法来阐明：1)分析DRL细胞质功能区，2)研究DRL膜内蛋白分解的作用和释放的DRL细胞质结构域的功能，3)鉴定DRL结合蛋白，以及4)表征DRL结合蛋白和候选DRL信号效应因子。

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.