A Cereblon signaling network in Wnt-driven cancers

Wnt驱动的癌症中的Cereblon信号网络 摘要 本研究的长期目标是研究Cereblon(CRBN)是如何调节Wnt信号转导的 并演示如何利用这一途径来靶向Wnt驱动的结直肠癌(CRC)。WNT 信号对肠道干细胞的维持至关重要，而这一途径的异常激活推动了 几乎所有初级保健方案的启动和进展。到目前为止，还没有抑制Wnt途径的药物被FDA- 获得批准，部分原因是缺乏可以绕过结直肠癌常见Wnt途径突变的可药物靶点。 在一项概念上的突破中，我们最近发表的发现显示，底物Cereblon(CRBN) CRL4CRBN E3泛素连接酶受体是血液系统恶性肿瘤的药物靶点，发挥着关键作用 在Wnt信号转导中的作用。我们发现CRBN促进了底物子集的降解， 包括酪蛋白激酶1α(CK1α)，Wnt信号的负调控因子和β-连环蛋白的关键成分 毁灭情结。此外，Wnt刺激可诱导CRBN与CK1α相互作用，从而促进其 泛素化和降解。此外，我们还发现CRBN在Wnt信号转导中的作用是保守的 人类细胞、小鼠肠道器官、斑马鱼和果蝇。这些研究证明了第一个 CRBN的内源性调节机制，并提供了一种控制Wnt途径活性的新手段， 与动物发育和疾病的相关性。该项目的目标是在体外、体外和体内使用 更好地了解临床相关抗癌靶点CRBN如何促进WNT的方法 信号转导。这三个具体目标是：1)确定WNT刺激激活的机制 CRBN；2)确定Wnt刺激的CRBN相互作用调节肿瘤的发生；3)阐明Wnt刺激的CRBN的作用 CRBN与Wnt依赖的癌症进展因为CRBN是一个经过充分研究的发展目标 从这项研究中获得的知识将有助于开发治疗血液恶性肿瘤的药物 更具选择性的小分子，以及为结直肠癌和其他WNT驱动的创新治疗策略提供建议 癌症。

A Cereblon Signaling Network in Wnt-driven Cancers Abstract The long-term objective of this study is to investigate how Cereblon (CRBN) regulates the Wnt signal transduction pathway and to demonstrate how this can be exploited to target Wnt-driven colorectal cancers (CRCs). Wnt signaling is essential for intestinal stem cell maintenance and aberrant activation of this pathway drives the initiation and progression of nearly all CRCs. To date, no drugs that inhibit the Wnt pathway have been FDA- approved, partly due to the lack of druggable targets that can bypass common Wnt pathway mutations in CRC. In a conceptual breakthrough, our recently published findings reveal that Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase that is a drug target in hematological malignancies, plays a critical role in Wnt signal transduction. We found that CRBN promotes the degradation of a subset of substrates, including Casein kinase 1α (CK1α), a negative regulator of Wnt signaling and a key component of the β-Catenin destruction complex. Moreover, Wnt stimulation induces the interaction of CRBN with CK1α to promote its ubiquitination and degradation. Furthermore, we showed that the role of CRBN in Wnt signaling is conserved in human cells, mouse intestinal organoids, zebrafish, and Drosophila. These studies demonstrate the first endogenous mechanism of CRBN regulation and provide a novel means of controlling Wnt pathway activity, with relevance for animal development and disease. The goal of this project is to use in vitro, ex vivo, and in vivo approaches to gain a better understanding of how the clinically relevant anti-cancer target, CRBN, promotes Wnt signal transduction. The three specific aims are to: 1) Identify the mechanisms by which Wnt stimulation activates CRBN; 2) Identify Wnt-stimulated CRBN interactors that regulate tumorigenesis; and 3) elucidate the role of CRBN in Wnt-dependent cancer progression. Because CRBN is a well-studied target for the development of drugs to treat hematological malignancies, the knowledge gained from this study will aid in the development of more selective small molecules as well as suggest innovative treatment strategies for CRC and other Wnt-driven cancers.