To condense or not to condense: Wnt regulation by centrosome-nucleated biomolecular condensates.
To condense or not to condense: Wnt regulation by centrosome-nucleated biomolecular condensates.
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DOI：
10.1073/pnas.2213905119
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发表时间：
2022-10-11
影响因子：
11.1
通讯作者：
Peifer, Mark
中科院分区：
文献类型：
--
作者：
Peifer, Mark
结直肠癌是全球癌症死亡的第三大原因，因此，了解推动癌症发展和进展的遗传变化至关重要。一个关键的突破发生在31年前，当时科学家克隆了肿瘤抑制基因腺瘤性结肠息肉病（APC），该基因在具有结肠癌易感性的家庭中发生突变。随后的工作表明，APC是破坏复合物（DC）的一部分，这是一种负调节关键发育信号通路Wnt通路的多蛋白机器（1）。Wnt信号调节所有动物的细胞命运选择和成体干细胞维持。然而，关键问题仍然是关于DC的工作机制。在PNAS中，Lach et al. (2)提供令人兴奋的见解。由于Wnt信号的力量，进化创造了在配体缺失时保持信号稳定的机制。在果蝇、小鼠和培养的结直肠癌细胞中的联合工作提供了重要的见解（3）。关键事件是调节Wnt效应子β-连环蛋白的稳定性（βcat;图1A）。当存在时，它与TCF家族转录因子一起激活Wnt靶基因。为了保持通路关闭，包括APC、另一种大型支架蛋白Axin和两种蛋白激酶-糖原合成酶激酶3（GSK 3）和酪蛋白激酶1-α（CK 1）-的多蛋白复合物捕获并磷酸化βcat，然后将其递送到E3泛素连接酶，靶向其进行蛋白水解破坏。在信号传导活跃的组织中，Wnt配体结合多蛋白受体，该受体降低DC活性，从而稳定细胞质和细胞核βcat并激活基因表达。在APC突变型结直肠癌中，即使信号关闭，βcat也保持稳定，组成性激活信号。这本教科书的描述听起来很整洁，给人的印象是Wnt调控机制已经解决。然而，关键问题依然存在。例如，单独的Axin可以作为支架将两种激酶带到βcat（4），使APC的功能不清楚。更令人困惑的是，一系列研究表明，四蛋白DC并不是故事的全部。当Axin在培养的细胞中表达时，它组装成多个“斑点”，APC、激酶和βcat被募集到这些斑点中（例如，参考文献1）。5和6;图1B）。Axin的DIX结构域介导蛋白质聚合（7），潜在地驱动含有每个DC蛋白的许多拷贝的斑点的组装（图1C）。
Colorectal cancer is the third leading cause of cancer deaths worldwide, and, thus, understanding genetic changes driving cancer development and progression is critical. A key breakthrough occurred 31 y ago when scientists cloned the tumor suppressor gene adenomatous polyposis coli (APC), mutated in families with a predisposition to colon cancer. Subsequent work revealed that APC is part of the destruction complex (DC), a multiprotein machine that negatively regulates a key developmental signaling pathway, the Wnt pathway (1). Wnt signaling regulates cell fate choice and adult stem cell maintenance in all animals. However, key questions remain about the mechanisms by which the DC works. In PNAS, Lach et al.(2) provide exciting insights. Because of the power of Wnt signaling, evolution crafted mechanisms to keep signaling firmly off in the ligand’s absence. Combined work in Drosophila, mice, and cultured colorectal cancer cells provided important insights (3). The key event is regulating stability of the Wnt effector β-catenin (βcat; Fig. 1A). When present, it works with TCF family transcription factors to activate Wnt target genes. To keep the pathway off, a multiprotein complex including APC, another large scaffolding protein—Axin—and two protein kinases—glycogen synthase kinase-3 (GSK3) and casein kinase 1-alpha (CK1)—captures and phosphorylates βcat, and then delivers it to an E3 ubiquitin ligase, targeting it for proteolytic destruction. In tissues where signaling is active, Wnt ligands bind a multiprotein receptor that turns down DC activity, thus stabilizing cytoplasmic and nuclear βcat and activating gene expression. In APC mutant colorectal cancers, βcat is stabilized even when signaling is off, activating signaling constitutively.This textbook description sounds tidy, leaving the impression that the Wnt regulatory mechanism is solved. However, key questions remain. For example, Axin alone can act as a scaffold to bring the two kinases to βcat (4), leaving APC’s function unclear. More puzzling, a series of studies suggested that a four-protein DC is not the whole story. When Axin is expressed in cultured cells, it assembles into multiple “puncta,” into which are recruited APC, the kinases, and βcat (eg, refs. 5 and 6; Fig. 1B). Axin’s DIX domain mediates protein polymerization (7), potentially driving assembly of puncta containing many copies of each DC protein (Fig. 1C).
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DOI：
10.1083/jcb.200808049
发表时间：
2009-01-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Rogers GC;Rusan NM;Roberts DM;Peifer M;Rogers SL
通讯作者：
Rogers SL
Axin 的相分离组织 β-连环蛋白破坏复合物
DOI：
10.1083/jcb.202012112
发表时间：
2021-04-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Nong J;Kang K;Shi Q;Zhu X;Tao Q;Chen YG
通讯作者：
Chen YG
影响因子：
4
作者：
Schwarz-Romond, Thomas;Metcalfe, Ciara;Bienz, Mariann
通讯作者：
Bienz, Mariann
影响因子：
5.2
作者：
Thorvaldsen, Tor Espen;Pedersen, Nina Marie;Stenmark, Harald
通讯作者：
Stenmark, Harald
DOI：
10.1073/pnas.1400568111
发表时间：
2014-04-15
影响因子：
11.1
作者：
Bazzi, Hisham;Anderson, Kathryn V.
通讯作者：
Anderson, Kathryn V.