Yang Eungi, Tacchelly-Benites Ofelia, Wang Zhenghan, Randall Michael P, Tian Ai, Benchabane Hassina, Freemantle Sarah, Pikielny Claudio, Tolwinski Nicholas S, Lee Ethan, Ahmed Yashi
Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755, USA.
Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755, USA.
Nat Commun. 2016 May 3;7:11430. doi: 10.1038/ncomms11430.
Wnt/β-catenin signalling directs fundamental processes during metazoan development and can be aberrantly activated in cancer. Wnt stimulation induces the recruitment of the scaffold protein Axin from an inhibitory destruction complex to a stimulatory signalosome. Here we analyse the early effects of Wnt on Axin and find that the ADP-ribose polymerase Tankyrase (Tnks)--known to target Axin for proteolysis-regulates Axin's rapid transition following Wnt stimulation. We demonstrate that the pool of ADP-ribosylated Axin, which is degraded under basal conditions, increases immediately following Wnt stimulation in both Drosophila and human cells. ADP-ribosylation of Axin enhances its interaction with the Wnt co-receptor LRP6, an essential step in signalosome assembly. We suggest that in addition to controlling Axin levels, Tnks-dependent ADP-ribosylation promotes the reprogramming of Axin following Wnt stimulation; and propose that Tnks inhibition blocks Wnt signalling not only by increasing destruction complex activity, but also by impeding signalosome assembly.
Wnt/β-连环蛋白信号传导在多细胞动物发育过程中指导基本过程，并且在癌症中可能被异常激活。Wnt刺激诱导支架蛋白Axin从抑制性破坏复合物募集到刺激性信号小体。在这里，我们分析了Wnt对Axin的早期影响，发现已知靶向Axin进行蛋白水解的ADP核糖基转移酶端锚聚合酶（Tnks）调节Wnt刺激后Axin的快速转变。我们证明，在基础条件下被降解的ADP核糖基化Axin库在果蝇和人类细胞中Wnt刺激后立即增加。Axin的ADP核糖基化增强了其与Wnt共受体LRP6的相互作用，这是信号小体组装中的关键步骤。我们认为，除了控制Axin水平外，Tnks依赖性ADP核糖基化还促进Wnt刺激后Axin的重编程；并提出抑制Tnks不仅通过增加破坏复合物活性来阻断Wnt信号传导，还通过阻碍信号小体组装来实现。
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