凝聚态中Axin的磷酸化抵消了tankyrase介导的降解作用。
Axin phosphorylation in condensates counteracts tankyrase-mediated degradation.
发表日期：2023 Sep 18
作者：
Katharina Klement, Martina Brückner, Dominic B Bernkopf
来源：
MEDICINE & SCIENCE IN SPORTS & EXERCISE
摘要：
Axin是原癌基因性Wnt/β-连环蛋白信号通路的中心负向调节因子，因为Axin凝结体为β-连环蛋白降解的多蛋白复合物组装提供了一个支架。Axin反过来通过tankyrase进行降解。因此，小分子tankyrase抑制剂通过稳定Axin来阻断Wnt信号传导，显示出在癌症治疗上的潜力。在这里，我们发现casein kinase 1α（CK1α）对Axin进行磷酸化，位于N-末端CK1的共识序列上，这种磷酸化被蛋白磷酸酶1（PP1）所拮抗。Axin凝结体通过富集CK1α而不是PP1来促进磷酸化。重要的是，这种磷酸化发生在tankyrase结合位点内，通过电荷或立体作用阻碍Axin和tankyrase的相互作用，并对抗tankyrase介导的Axin降解。因此，所呈现的数据提出了一个调节Axin稳定性的新机制，对Wnt信号通路、癌症治疗和生物分子凝聚体的自组织具有重要意义。©2023年。由生物学家有限公司出版。
Axin is a central negative regulator of the proto-oncogenic Wnt/β-catenin signaling pathway, as axin condensates provide a scaffold for the assembly of a multiprotein complex degrading β-catenin. Axin in turn is degraded via tankyrase. Consequently, small molecule tankyrase inhibitors block Wnt signaling by stabilizing axin, revealing potential for cancer therapy. Here, we discover phosphorylation of axin by casein kinase 1α (CK1α) at an N-terminal CK1 consensus motif, which was antagonized by protein phosphatase 1 (PP1). Axin condensates promoted phosphorylation by enriching CK1α over PP1. Importantly, the phosphorylation took place within the tankyrase-binding site, hindered axin-tankyrase interaction electrostatically and/or sterically, and counteracted tankyrase-mediated degradation of axin. Thus, the presented data propose a novel mechanism regulating axin stability, with implications for Wnt signaling, cancer therapy and self-organization of biomolecular condensates.© 2023. Published by The Company of Biologists Ltd.