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起关键作用，其构成激活直接涉及人类癌症。非规范的Wnt通路也重要地参与包括平面细胞极性（PCP）和趋同扩展在内的发育，与Wnt 2-catenin信号通路共享包括卷曲（Fz）受体和凌乱（Dsh/Dvl）的成分。然而，Dsh/Dvl下游的信号通路分化，激活了截然不同的生化途径和生物学结果。该应用程序研究了Wnt信号特异性的分子方面，利用了涉及哺乳动物和果蝇系统的互补方法和专业知识。使用kinome shRNA筛选，我们鉴定了两种新的Dsh激酶，dWnk和dCDKL。我们的初步研究表明，这些激酶分别在规范和PCP途径中特异性起作用。在Aim 1中，我们提出进一步表征果蝇Wnk激酶在wnt通路特异性反应中的作用。在Aim 2中，我们将研究哺乳动物Wnk激酶在Wnt规范信号传导和Wnt驱动的癌细胞中的作用。在Aim 3中，我们将描述CDKL激酶在wnt信号通路反应中的作用。这些研究将阐明Wnt通路的新成分，从而更好地理解Wnt通路规范的进化守恒和/或分化，并可能为Wnt激活的人类肿瘤细胞确定新的治疗靶点。调查人员之间的密切合作互动加强了我们的努力，他们的专业知识和相互关联的努力有力地补充和帮助了这些调查。

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.