Secreted Frizzled-Related Proteins and Wnt Signaling

分泌的卷曲相关蛋白和 Wnt 信号传导

• 批准号: 7338283
• 负责人: JEFFREY RUBIN
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7338283
• 关键词: Secreted; Frizzled; Related; Proteins; Wnt

The focus of my lab has broadened to include both the study of secreted Frizzled-related proteins (sFRPs) and cellular responses to Wnt stimulation. We have embarked on the purification of Wnt proteins, not only to provide reagents to facilitate the analysis of sFRP function, but to foster investigation of Wnt activity and association signaling. Defining the specificity of Wnt/Frizzled (Fz)/sFRP interactions is one of our primary goals. Currently, we have purified four recombinant sFRP and have made progress in the isolation of three Wnt proteins. We also identified a cell line with a low background of Wnt/Fz expression, and separately introduced three Fzs into these cells to assist our study of Wnt/Fz/sFRP binding and signaling. Recently, we initiated a collaboration to investigate the role of R-spondins in the stimuation of Wnt/beta-catenin signaling and tumorigenesis. We developed model systems to examine Wnt-dependent changes in cell shape and motility, and non-canonical Wnt signaling involved in these processes. We have determined that Wnt-3a stimulates the assembly of fibronectinn (FN) fibrils, a phenomenon that likely contributes to cell spreading and movement.Our longstanding study of sFRP-1 has continued in a variery of context. An Sfrp1 null mouse model has been developed, and we are sharing it with multiple labs to better understand the physiological activities of sFRP-1. In various experimental systems, we have been comparing and contrasting the effects of sFRP-1 and Dickkopf-1 (Dkk-1). While both inhibit the beta-catenin pathway, our results suggest that Dkk-1 might enhance non-canonical signaling in situations where it is blocked by sFRP-1. Besides the well-established role of sFRP-1 as a regulator of Wnt signaling, we are exploring the possibility that it has novel binding partners and additional mechanisms of action. Taken together, our sFRP and Wnt studies will contribute to a better understanding of their roles in cancer, development and tissue homeostasis.

我的实验室的重点已经扩大到包括分泌卷曲相关蛋白（sFRPs）和细胞对Wnt刺激的反应的研究。我们已经开始了Wnt蛋白的纯化，不仅是为了提供试剂来促进sFRP功能的分析，而且是为了促进Wnt活性和关联信号的研究。确定Wnt/ frizzed (Fz)/sFRP相互作用的特异性是我们的主要目标之一。目前，我们已经纯化了4个重组sFRP，并在3个Wnt蛋白的分离方面取得了进展。我们还鉴定了一个低背景Wnt/Fz表达的细胞系，并分别将三个Fz引入这些细胞中，以协助我们研究Wnt/Fz/sFRP结合和信号传导。最近，我们发起了一项合作研究R-spondins在刺激Wnt/ β -连环蛋白信号传导和肿瘤发生中的作用。我们开发了模型系统来检查细胞形状和运动中Wnt依赖的变化，以及参与这些过程的非规范Wnt信号。我们已经确定Wnt-3a刺激纤维连接蛋白（FN）原纤维的组装，这种现象可能有助于细胞的扩散和运动。我们对sFRP-1的长期研究在各种背景下继续进行。我们已经建立了一个srp1缺失小鼠模型，我们正在与多个实验室共享该模型，以便更好地了解sFRP-1的生理活动。在不同的实验系统中，我们已经比较和对比了sFRP-1和Dickkopf-1 （Dkk-1）的作用。虽然两者都抑制β -连环蛋白通路，但我们的研究结果表明，Dkk-1可能在被sFRP-1阻断的情况下增强非规范信号传导。除了已确定的sFRP-1作为Wnt信号调节因子的作用外，我们正在探索它具有新的结合伙伴和其他作用机制的可能性。综上所述，我们的sFRP和Wnt研究将有助于更好地理解它们在癌症、发育和组织稳态中的作用。