Regulation of Wnt Pathway Specificity

Wnt 通路特异性的调节

基本信息

批准号：
9113436
负责人：
Stuart A Aaronson
金额：
$ 6.19万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113436
关键词：
Address Affect Biochemical Biochemical Pathway Biological CSNK1A1 gene Cells Complement Complex Cyclin-Dependent Kinases Data Defect Development Disease Dissection Drosophila genus Embryonic Development Family Family member Genetic study Glycogen Synthase Kinase 3 Goals Growth Human Investigation Joints Knowledge Lead Ligands Link Malignant Neoplasms Mammals Mediating Membrane Molecular Organ Organogenesis Outcome Pathway interactions Pattern Phosphorylation Phosphotransferases Play Polycystic Kidney Diseases Proteins Proto-Oncogenes RNA Interference Recruitment Activity Regulation Research Personnel Role Signal Pathway Signal Transduction Specificity System Time Tissues Tumor Suppressor Proteins Vertebrates angiogenesis base blastomere structure cancer cell ciliopathy convergent extension loss of function neoplastic cell new therapeutic target novel planar cell polarity receptor receptor density response small hairpin RNA tumor

项目摘要

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.

描述（由申请人提供）：Wnt典型信号在胚胎发育和细胞命运决策中起关键作用及其组成型激活已直接与人类癌症有关。非规范的Wnt途径（包括平面细胞极性（PCP）和收敛延伸）的发育中也很重要，共享具有Wnt 2-catenin信号传导的组件，包括卷曲（FZ）受体和味觉（DSH/DVL）。然而，途径信号传导在DSH/DVL的下游差异，以激活明显不同的生化途径和生物学结果。该应用研究了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。使用Kinome shrna屏幕，我们确定了两个新型的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途径中发挥作用。在AIM 1中，我们建议在Wnt-pathway特定响应中进一步表征果蝇WNK激酶。在AIM 2中，我们将研究哺乳动物WNK激酶在Wnt典型信号传导和WNT驱动癌细胞中的作用。在AIM 3中，我们将表征CDKL激酶在Wnt信号途径响应中的作用。这些研究应阐明Wnt途径的新成分，使人们更好地了解Wnt途径规范的进化保护和/或差异，并可能确定WNT激活的人类肿瘤细胞的新治疗靶标。调查人员之间的紧密协作互动可以加强我们的努力，他们的专业知识和相互关联的努力强烈补充并有助于为这些调查提供信息。