Regulation of Wnt Pathway Specificity

描述（由申请人提供）：Wnt经典信号传导在胚胎发育和细胞命运决定中起关键作用，其组成性激活直接涉及人类癌症。非经典Wnt途径也重要地参与发育，包括平面细胞极性（PCP）和会聚延伸，与Wnt 2-连环蛋白信号传导共享组分，包括卷曲（Fz）受体和Dishevelled（Dsh/Dvl）。然而，通路信号传导在Dsh/Dvl下游发散以激活显著不同的生化通路和生物学结果。本申请研究Wnt信号特异性的分子方面，利用互补的方法和专业知识，涉及哺乳动物和果蝇系统。使用激酶组shRNA筛选，我们已经确定了两种新的Dsh激酶，dWnk和dCDKL。我们的初步研究表明，这些激酶特异性功能的经典和PCP途径，分别。在目的1中，我们建议进一步表征果蝇Wnk激酶在Wnt通路特异性反应中的作用。在目标2中，我们将研究哺乳动物Wnk激酶在Wnt经典信号传导和Wnt驱动的癌细胞中的作用。在目标3中，我们将描述CDKL激酶在Wnt信号通路反应中的作用。这些研究应该阐明Wnt通路的新组分，导致更好地理解Wnt通路规范的进化保守性和/或分歧，并可能确定Wnt激活的人肿瘤细胞的新治疗靶点。调查人员之间的密切协作互动加强了我们的努力，他们的专门知识和相互关联的努力有力地补充了这些调查，并有助于为这些调查提供信息。

DESCRIPTION (provided by applicant): Wnt canonical signaling plays critical roles in embryonic development and cell fate decisions and its constitutive activation has been directly implicated in human cancer. The noncanonical Wnt pathway, also importantly involved in development including planar cell polarity (PCP) and convergent extension, shares components with Wnt 2-catenin signaling including the Frizzled (Fz) receptors and Dishevelled (Dsh/Dvl). However, pathway signaling diverges downstream of Dsh/Dvl to activate strikingly different biochemical pathways and biological outcomes. This application investigates the molecular aspects of Wnt signaling specificity, taking advantage of complementary approaches and expertise involving both mammalian and Drosophila systems. Using a kinome shRNA screen we have identified two novel Dsh kinases, dWnk and dCDKL. Our preliminary studies indicate that these kinases specifically function in canonical and PCP pathways, respectively. In Aim 1, we propose to further characterize Drosophila Wnk kinase in Wnt-pathway specific responses. In Aim 2, we will investigate the role of mammalian Wnk kinases in Wnt canonical signaling and in Wnt-driven cancer cells. In Aim 3, we will characterize the role of CDKL kinases in Wnt-signaling pathway responses. These investigations should elucidate novel components of Wnt pathways, lead to a better understanding of the evolutionary conservation and/or divergence of Wnt pathway specification, and possibly identify new therapeutic targets for Wnt activated human tumor cells. Our efforts are enhanced by close collaborative interactions among investigators, whose expertise and interrelated efforts strongly complement and help to inform these investigations.