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Centrosomes are required for proper β-catenin processing and Wnt response.
Molecular Biology of the Cell ( IF 3.3 ) Pub Date : 2020-06-17 , DOI: 10.1091/mbc.e20-02-0139
Setu M Vora 1 , Jan S Fassler 1 , Bryan T Phillips 1
Affiliation  

The Wnt/β-catenin signaling pathway is central to metazoan development and routinely dysregulated in cancer. Wnt/β-catenin signaling initiates transcriptional reprogramming upon stabilization of the transcription factor β-catenin, which is otherwise posttranslationally processed by a destruction complex and degraded by the proteasome. Since various Wnt signaling components are enriched at centrosomes, we examined the functional contribution of centrosomes to Wnt signaling, β-catenin regulation, and posttranslational modifications. In HEK293 cells depleted of centrosomes we find that β-catenin synthesis and degradation rates are unaffected but that the normal accumulation of β-catenin in response to Wnt signaling is attenuated. This is due to accumulation of a novel high-molecular-weight form of phosphorylated β-catenin that is constitutively degraded in the absence of Wnt. Wnt signaling operates by inhibiting the destruction complex and thereby reducing destruction complex-phosphorylated β-catenin, but high-molecular-weight β-catenin is unexpectedly increased by Wnt signaling. Therefore these studies have identified a pool of β-catenin effectively shielded from regulation by Wnt. We present a model whereby centrosomes prevent inappropriate β-catenin modifications that antagonize normal stabilization by Wnt signals.

中文翻译:

适当的β-catenin处理和Wnt反应需要离心体。

Wnt /β-catenin信号通路是后生动物发展的关键,在癌症中通常失调。Wnt /β-catenin信号转导在转录因子β-catenin稳定后启动转录重编程,否则它会被破坏复合物进行翻译后加工并被蛋白酶体降解。由于各种Wnt信号成分在中心体富集,我们检查了中心体对Wnt信号,β-catenin调节和翻译后修饰的功能性贡献。在耗竭着中心体的HEK293细胞中,我们发现β-catenin的合成和降解率不受影响,但是响应Wnt信号的β-catenin的正常积累却被减弱了。这是由于新型的高分子量形式的磷酸化β-catenin的积累,该结构在Wnt不存在的情况下会被组成性降解。Wnt信号传导通过抑制破坏复合物从而减少破坏复合物磷酸化的β-catenin而起作用,但是高分子量的β-catenin被Wnt信号传导意外地增加。因此,这些研究已经鉴定出有效屏蔽Wnt调节的β-catenin库。我们提出了一个模型,其中中心体可以防止不适当的β-catenin修饰,从而通过Wnt信号拮抗正常的稳定性。因此,这些研究已经鉴定出有效屏蔽Wnt调节的β-catenin库。我们提出了一个模型,其中中心体可防止不适当的β-catenin修饰,从而通过Wnt信号拮抗正常的稳定作用。因此,这些研究已经鉴定出有效屏蔽Wnt调节的β-catenin库。我们提出了一个模型,其中中心体可防止不适当的β-catenin修饰,从而通过Wnt信号拮抗正常的稳定作用。
更新日期:2020-06-17
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