Regulation of Wnt Pathway Specificity

描述(由申请人提供)：WNT规范信号在胚胎发育和细胞命运决定中发挥关键作用，其结构性激活已直接与人类癌症有关。非典型的Wnt途径也参与了包括平面细胞极性(PCP)和汇聚延伸在内的发育过程，它与Wnt2-catenin信号通路具有相同的成分，包括FrizzledFz受体和disheveled(DshVL)。然而，通路信号在Dsh/DVL下游分化，从而激活了截然不同的生化途径和生物学结果。这项应用研究Wnt信号特异性的分子方面，利用涉及哺乳动物和果蝇系统的互补方法和专业知识。利用动态组shRNA筛选，我们鉴定了两个新的dsh激酶，dWnk和dCDKL。我们的初步研究表明，这些激酶分别在规范途径和PCP途径中特异发挥作用。在目标1中，我们建议进一步表征果蝇WNK激酶在Wnt途径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规范信号和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。这些研究将有助于阐明Wnt通路的新成分，更好地理解Wnt通路规范的进化保守性和/或差异性，并可能为Wnt激活的人类肿瘤细胞寻找新的治疗靶点。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和帮助这些调查工作。

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.