Inhibition of the Wnt Receptor Complex by the Tumor Suppressor Adenomatous Polyposis Coli

项目摘要 抑癌基因腺瘤性息肉病结肠对Wnt受体激活的抑制作用 这项研究的长期目标是调查肿瘤抑制因子腺瘤是如何 大肠息肉病(APC)通过调节Wnt受体抑制Wnt信号转导途径 复合体(信号体)，并演示如何利用这一点来靶向APC突变的结直肠 癌症(CRC)。WNT信号对肠道干细胞的维持至关重要，而异常 这一途径的激活，最常发生在APC的突变失活，触发 绝大多数社区合作伙伴的发展。在WNT信号的经典模型中，WNT信号的唯一作用 APC的作用是破坏Wnt途径中的关键转录激活因子--β-连环蛋白的稳定性。然而，我们的 最近发表的研究结果揭示了一种额外的、全新的功能-APC防止 信号小体的内化和随之而来的激活，这是进化中的一个新角色 保守的。我们的研究结果表明：1)APC的可诱导性丢失之后很快就出现了非配体依赖性 信号体激活；2)LRP6(信号体)的耗尽或抗体介导的抑制 成分)抑制β-连环蛋白的稳定，抑制Wnt靶基因的转录激活， 3)在APC突变细胞中，Wnt受体的内吞作用 Wnt信号的异常激活所必需的。这个项目的目标是使用体外，体外， 以及体内方法以更好地了解APC如何抑制信号体激活 在生理条件下，并确定信号体的异常激活是如何基础的 肿瘤中APC失活的后果。这三个具体目标是：1)阐明 APC丢失促进CRC细胞内信号小体组装的机制；2)鉴定APC 突变的CRC细胞对LRP6最敏感；以及3)测试LRP6灭活的效果 结直肠癌体内致瘤性的研究。因为APC通过分子机制来阻止 Wnt信号的异常激活对于我们理解结直肠癌的发生具有重要意义。 从这项研究中获得的知识将有助于开发新的治疗策略 结直肠癌和其他由Wnt驱动的癌症的治疗。

Project Summary Inhibition of Wnt Receptor Activation by the Tumor Suppressor Adenomatous Polyposis Coli The long-term objective of this study is to investigate how the tumor suppressor Adenomatous polyposis coli (APC) inhibits the Wnt signal transduction pathway by regulating the Wnt receptor complex (signalosome) and to demonstrate how this can be exploited to target APC mutant colorectal cancers (CRCs). Wnt signaling is essential for intestinal stem cell maintenance, whereas aberrant activation of this pathway, which occurs most frequently through mutational inactivation of APC, triggers the development of the vast majority of CRCs. In the classical model for Wnt signaling, the sole role of APC is to destabilize the key transcriptional activator in the Wnt pathway, beta-catenin. However, our recently published findings reveal an additional and entirely new function – APC prevents the internalization and consequent activation of the signalosome, a novel role that is evolutionarily conserved. We have shown that: 1) inducible loss of APC is rapidly followed by ligand-independent signalosome activation; 2) depletion or antibody-mediated inhibition of LRP6 (a signalosome component) inhibits the stabilization of beta-catenin, the transcriptional activation of Wnt target genes, and the proliferation of APC mutant cells; and 3) in APC mutant cells, endocytosis of Wnt receptors is required for the aberrant activation of Wnt signaling. The goal of this project is to use in vitro, ex vivo, and in vivo approaches to gain a better understanding of how APC inhibits signalosome activation under physiological conditions and to determine how aberrant activation of the signalosome underlies the consequences of APC inactivation in tumors. The three specific aims are to: 1) elucidate the mechanism by which APC loss promotes signalosome assembly in CRC cells; 2) identify the APC mutant CRC cells most susceptible to LRP6 inactivation; and 3) test the efficacy of LRP6 inactivation on CRC tumorigenicity in vivo. Because the molecular mechanisms by which APC prevents the aberrant activation of Wnt signaling are important for our understanding of colorectal carcinogenesis, the knowledge gained from this study will aid in the development of new therapeutic strategies for the treatment of CRC and other Wnt-driven cancers.