Scribble sub-cellular localization modulates recruitment of YES1 to regulate YAP1 phosphorylation.
Scribble sub-cellular localization modulates recruitment of YES1 to regulate YAP1 phosphorylation.
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DOI：
10.1016/j.chembiol.2021.02.019
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发表时间：
2021-03
影响因子：
8.6
通讯作者：
Dongyu Zhao;Zhangyuan Yin;M. Soellner;Brent R. Martin
中科院分区：
文献类型：
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作者：
Dongyu Zhao;Zhangyuan Yin;M. Soellner;Brent R. Martin
多结构域支架蛋白Scribble （Scrib）调节细胞极性和细胞-细胞连接处的生长信号。在上皮性癌症中，Scrib的错定位和过表达矛盾地将Scrib从基底侧肿瘤抑制因子转化为致瘤性的细胞质驱动因子。为了解决Scrib （mis）定位的功能，在极化上皮细胞中进行了Scrib- halotag融合基因组工程。上皮间充质转录因子Snail的表达取代了细胞连接处的Scrib-HaloTag，反映了在癌症中观察到的错误定位。有趣的是，蜗牛表达促进yes相关蛋白-1 （YAP1）的核定位，而不依赖于河马通路调节的YAP-S127磷酸化。此外，Scrib HaloPROTAC降解会减弱YAP1-Y357的磷酸化。halo -配体亲和纯化质谱分析发现Src家族激酶YES1是一个错误定位的Scrib相互作用伙伴，优先招募激酶活性和开放的整体构象（αC螺旋in）。总之，错位Scrib通过脚手架活性YES1增强YAP1磷酸化。
The multi-domain scaffolding protein Scribble (Scrib) regulates cell polarity and growth signaling at cell-cell junctions. In epithelial cancers, Scrib mislocalization and overexpression paradoxically transform Scrib from a basolateral tumor suppressor to a cytosolic driver of tumorigenicity. To address the function of Scrib (mis)localization, a Scrib-HaloTag fusion was genome engineered in polarized epithelial cells. Expression of the epithelial to mesenchymal transcription factor Snail displaced Scrib-HaloTag from cell junctions, mirroring the mislocalization observed in cancers. Interestingly, Snail expression promotes Yes-associated protein-1 (YAP1) nuclear localization independent of hippo pathway-regulated YAP-S127 phosphorylation. Furthermore, Scrib HaloPROTAC degradation attenuates YAP1-Y357 phosphorylation. Halo-ligand affinity purification mass spectrometry analysis identified the Src family kinase YES1 as a mislocalized Scrib interaction partner, preferentially recruiting the kinase active and open global conformation (αC helix in). Altogether, mislocalized Scrib enhances YAP1 phosphorylation by scaffolding active YES1.