MOLECULAR BASIS OF THE WNT SIGNALING PATHWAY

拟议研究的目标是使用结构和 生物物理方法研究潜在的分子机制 Wnt信号通路的特异性调控和靶向相互作用。 WNT信号在胚胎发育过程中发挥着重要作用 调节细胞生长。WNT信号的不适当激活已被 与癌症和其他人类疾病有关。蓬头垢面是一个重要的 WNT路径上的球员。它传递来自膜结合的Wnt的信号 下游伙伴的受体。序列分析揭示了两部新小说 蓬乱的蛋白质结构域：DEP和DIX结构域。据信， DEP结构域与膜结合受体结合，而DIX结构域 与下游组件交互。蛋白质核磁共振光谱学将用于 确定两个结构域的结构和基本化学性质 两个域和它们的绑定伙伴之间的交互将是 通过结构和生物物理方法进行分析。Axin，一种蛋白质 下游的蓬头垢面，还包含一个DIX域。它是被假设的 Wnt信号通过异二聚化从蓬乱传递到轴蛋白 在两个DIX结构域中。这一假设将通过进一步的分析来检验 Axin DIX结构域和DIX杂二聚体复合体的结构。这个 申请人建议，这些研究将揭示第一个结构和 有关DEP和DIX域的功能信息，并最终可能提供 对可干扰药物的药剂发展的见解 人类疾病中特定的Wnt信号事件。

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.