Developmental, Stem Cell and Cancer Biology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
Handb Exp Pharmacol. 2021;269:137-173. doi: 10.1007/164_2021_522.
WNT/CTNNB1 signaling is crucial for balancing cell proliferation and differentiation in all multicellular animals. CTNNB1 accumulation is the hallmark of WNT/CTNNB1 pathway activation and the key downstream event in both a physiological and an oncogenic context. In the absence of WNT stimulation, the cytoplasmic and nuclear levels of CTNNB1 are kept low because of its sequestration and phosphorylation by the so-called destruction complex, which targets CTNNB1 for proteasomal degradation. In the presence of WNT proteins, or as a result of oncogenic mutations, this process is impaired and CTNNB1 levels become elevated.Here we discuss recent advances in our understanding of destruction complex activity and inactivation, focusing on the individual components and interactions that ultimately control CTNNB1 turnover (in the "WNT off" situation) and stabilization (in the "WNT on" situation). We especially highlight the insights gleaned from recent quantitative, image-based studies, which paint an unprecedentedly detailed picture of the dynamic events that control destruction protein complex composition and function. We argue that these mechanistic details may reveal new opportunities for therapeutic intervention and could result in the destruction complex re-emerging as a target for therapy in cancer.
WNT/CTNNB1 信号通路对于所有多细胞动物中细胞增殖和分化的平衡至关重要。CTNNB1 的积累是 WNT/CTNNB1 通路激活的标志，也是生理和致癌环境中关键的下游事件。在没有 WNT 刺激的情况下，由于其被所谓的破坏复合物隔离和磷酸化，CTNNB1 的细胞质和核内水平保持较低，破坏复合物靶向 CTNNB1 进行蛋白酶体降解。在存在 WNT 蛋白的情况下，或者由于致癌突变，这个过程受到干扰，CTNNB1 水平升高。在这里，我们讨论了我们对破坏复合物活性和失活的最新理解进展，重点介绍了最终控制 CTNNB1 周转率（在“WNT 关闭”情况下）和稳定性（在“WNT 开启”情况下）的单个组件和相互作用。我们特别强调了从最近的定量、基于图像的研究中获得的见解，这些研究描绘了控制破坏蛋白复合物组成和功能的动态事件的前所未有的详细情况。我们认为，这些机制细节可能会揭示出新的治疗干预机会，并可能导致破坏复合物重新成为癌症治疗的靶点。
