MOLECULAR BASIS OF THE WNT SIGNALING PATHWAY

拟议研究的目的是利用结构和 生物物理学方法来研究潜在的分子机制， Wnt信号通路的特异性调节和靶向相互作用。 Wnt信号传导在胚胎发育和发育过程中发挥着重要作用 调节细胞生长。Wnt信号传导的不适当激活已经被证明是一种重要的信号传导机制。 与癌症和其他人类疾病有关。衣冠不整是一个重要的 Wnt途径的参与者。它将来自膜结合Wnt的信号 受体到下游的合作伙伴。序列分析揭示了两个新的 Dishevelled中的蛋白质结构域：DEP和DIX结构域。据信 DEP结构域与膜结合受体结合， 与下游组件相互作用。蛋白质NMR光谱将用于 确定两个结构域的结构和基本化学性质 这两个结构域和它们的结合伴侣之间的相互作用将是 通过结构和生物物理方法分析。Axin是一种 在Dishevelled的下游，也含有DIX结构域。已经假设 Wnt信号通过异源二聚化从Dishevelled传递到Axin 两个DIX域。这一假设将通过进一步分析来检验。 轴蛋白DIX结构域和DIX异二聚体复合物的结构。的 申请人建议，这些研究将揭示第一个结构和 关于DEP和DIX域的功能信息，并最终可以提供 对药物制剂的发展的见解，可以干扰 在人类疾病中的特异性Wnt信号传导事件。

The objective of the proposed studies is to use structural and biophysical methods to investigate the molecular mechanisms underlying the specific regulatory and targeting interactions of the Wnt signaling pathway. Wnt signaling plays an important role in embryonic development and in the regulation of cell growth. Inappropriate activation of Wnt signaling has been implicated in cancers and other human diseases. Dishevelled is an important player in the Wnt pathway. It relays the signal from the membrane-bound Wnt receptors to downstream partners. Sequence analysis revealed two new novel protein domains in Dishevelled: the DEP and DIX domains. It is believed that the DEP domain binds to the membrane-bound receptor and that the DIX domain interacts with downstream components. Protein NMR spectroscopy will be used to determine the structures of the two domains and the fundamental chemical nature of the interactions between both domains and their binding partners will be analyzed by structural and biophysical methods. Axin, one of the proteins downstream of Dishevelled, also contains a DIX domain. It has been hypothesized that the Wnt signal passes from Dishevelled to Axin through heterodimerization of the two DIX domains. This hypothesis will be examined by further analysis of the structures of the Axin DIX domain and the DIX heterodimer complex. The applicant suggests that these studies will reveal the first structural and functional information about DEP and DIX domains and, ultimately, may provide insights for the development of pharmaceutical agents that can interfere with specific Wnt signaling events in human disease.