The Adenomatous polyposis coli tumour suppressor is essential for Axin complex assembly and function and opposes Axin's interaction with Dishevelled.
The Adenomatous polyposis coli tumour suppressor is essential for Axin complex assembly and function and opposes Axin's interaction with Dishevelled.
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DOI：
10.1098/rsob.110013
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发表时间：
2011-11
期刊：
影响因子：
5.8
通讯作者：
Bienz M
中科院分区：
文献类型：
--
作者：
Mendoza-Topaz C;Mieszczanek J;Bienz M
大多数结直肠癌病例与结肠腺瘤性息肉病（APC）肿瘤抑制因子的突变失活有关。APC通过使Axin能够促进Wnt信号传导效应物β-连环蛋白（果蝇中的Armadillo）的降解来下调Wnt信号传导。这取决于Axin的DIX结构域，其聚合允许其形成动态蛋白质组装体（“降解体”）。轴蛋白在Wnt信号传导后通过与Dishevelled的DIX结构域的异源聚合而失活，这将其募集到膜相关的“信号体”中。APC如何促进Axin的功能尚不清楚，特别是因为已经报道APC的功能可以通过Axin的过表达而绕过。检查apc无效突变果蝇组织，我们发现APC是Axin降解酶体组装所需的，其本身对于Armadillo下调是必需的。降解酶体组装在APC突变癌细胞中也减弱。值得注意的是，在APC不存在的情况下，Axin变得倾向于Dishevelled依赖性质膜募集，表明APC在对抗Axin与Dishevelled的相互作用中起关键作用。事实上，共表达实验揭示，APC从Axin组装体置换Dishevelled，在Wnt不存在的情况下促进降解体超过信号体形成。因此，APC使Axin以两种方式发挥作用-通过使其DIX依赖性自组装，并通过对抗其DIX依赖性共聚与Dishevelled和随后的失活。
Most cases of colorectal cancer are linked to mutational inactivation of the Adenomatous polyposis coli (APC) tumour suppressor. APC downregulates Wnt signalling by enabling Axin to promote the degradation of the Wnt signalling effector β-catenin (Armadillo in flies). This depends on Axin's DIX domain whose polymerization allows it to form dynamic protein assemblies (‘degradasomes’). Axin is inactivated upon Wnt signalling, by heteropolymerization with the DIX domain of Dishevelled, which recruits it into membrane-associated ‘signalosomes’. How APC promotes Axin's function is unclear, especially as it has been reported that APC's function can be bypassed by overexpression of Axin. Examining apc null mutant Drosophila tissues, we discovered that APC is required for Axin degradasome assembly, itself essential for Armadillo downregulation. Degradasome assembly is also attenuated in APC mutant cancer cells. Notably, Axin becomes prone to Dishevelled-dependent plasma membrane recruitment in the absence of APC, indicating a crucial role of APC in opposing the interaction of Axin with Dishevelled. Indeed, co-expression experiments reveal that APC displaces Dishevelled from Axin assemblies, promoting degradasome over signalosome formation in the absence of Wnts. APC thus empowers Axin to function in two ways—by enabling its DIX-dependent self-assembly, and by opposing its DIX-dependent copolymerization with Dishevelled and consequent inactivation.
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影响因子：
56.9
作者：
Behrens, J;Jerchow, BA;Birchmeier, W
通讯作者：
Birchmeier, W
DOI：
10.1083/jcb.146.6.1303
发表时间：
1999-09-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
McCartney BM;Dierick HA;Kirkpatrick C;Moline MM;Baas A;Peifer M;Bejsovec A
通讯作者：
Bejsovec A
影响因子：
9.2
作者：
de la Roche, Marc;Bienz, Mariann
通讯作者：
Bienz, Mariann
影响因子：
4.6
作者：
McCartney, Brooke M.;Price, Meredith H.;Peifer, Mark
通讯作者：
Peifer, Mark
影响因子：
9.2
作者：
Hart, MJ;de los Santos, R;Polakis, P
通讯作者：
Polakis, P