Structural basis and molecular mechanism of biased GPBAR signaling in regulating NSCLC cell growth via YAP activity.
Structural basis and molecular mechanism of biased GPBAR signaling in regulating NSCLC cell growth via YAP activity.
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GPBAR信号偏向通过YAP活性调节NSCLC细胞生长的结构基础和分子机制
DOI：
10.1073/pnas.2117054119
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发表时间：
2022-07-19
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
G蛋白偶联胆汁酸受体（GPBAR）是天然的胆汁酸受体和用于治疗代谢性疾病的治疗靶标。然而，特定的胆汁酸被怀疑促进癌症进展。我们发现，GPBAR的不同Gs/arrestin偏向信号在非小细胞肺癌（NSCLC）细胞活力中起着关键作用。具体地，β-抑制蛋白偏向的GPBAR激动剂R399通过促进雅普（Yes-associate Protein）活化来刺激细胞生长。相反，由脱氧胆酸和INT-777触发的GPBAR激活（显示对Gs信号传导的偏好）抑制癌细胞进展。此外，我们描绘了GPBAR的β-arrestin偏好和促肿瘤活性的关键结构决定因素，并确定GRK 2/GRK 5对GPBAR的磷酸化有助于β-arrestin偏好信号传导。这些结果可能有助于合理设计具有抗癌益处的GPBAR靶向药物。G蛋白偶联胆汁酸受体（GPBAR）是胆汁酸的膜受体，是肝脏-胆汁酸-微生物群-器官轴调节代谢和其他病理生理过程的驱动力。虽然GPBAR是一系列代谢和神经退行性疾病的重要治疗靶点，但其激活也被发现与致癌作用有关，导致潜在的副作用。在这里，通过功能筛选，我们发现两种特异性GPBAR激动剂R399和INT-777在体外和体内对非小细胞肺癌（NSCLC）细胞的生长和凋亡表现出明显不同的调节作用。进一步的机制研究表明，R399诱导的GPBAR激活对β-arrestin 1信号有明显的偏好，从而促进雅普信号的激活，刺激细胞增殖。相反，INT-777优先激活GPBAR-Gs信号传导，从而灭活雅普，抑制细胞增殖并诱导细胞凋亡。GRK 2在S310/S321/S323/S324位点磷酸化GPBAR有助于R399诱导GPBAR-β-arrestin 1缔合。R399结合的GPBAR-Gs复合物的冷冻电子显微镜（cryo-EM）结构使我们能够鉴定GPBAR中负责抑制蛋白信号传导偏倚和癌细胞增殖的关键相互作用残基和关键构象变化。总之，我们证明了在NSCLC细胞模型中，不同的激动剂可以通过偏置GPBAR信号传导和雅普活性的控制来调节细胞生长和凋亡的不同功能。所描述的机制和结构基础可能有助于合理设计具有代谢和抗癌益处的GPBAR靶向药物。
The G protein–coupled bile acid receptor (GPBAR) is the native bile acid receptor and therapeutic target for treating metabolic diseases. However, specific bile acids are suspected to promote cancer progression. We showed that different Gs/arrestin-biased signaling of GPBAR played key roles in non–small cell lung cancer (NSCLC) cell viability. Specifically, β-arrestin–biased GPBAR agonist R399 stimulated cell growth through promoting YAP (Yes-associate Protein) activation. Conversely, GPBAR activation triggered by deoxycholic acid and INT-777, which showed a preference to Gs signaling, inhibited cancer cell progression. Moreover, we delineated key structural determinants of β-arrestin bias and protumor activity of GPBAR and identified that phosphorylation of GPBAR by GRK2/GRK5 contributed to β-arrestin–biased signaling. These results may facilitate rational design of GPBAR-targeting drugs with anticancer benefits. The G protein–coupled bile acid receptor (GPBAR) is the membrane receptor for bile acids and a driving force of the liver–bile acid–microbiota–organ axis to regulate metabolism and other pathophysiological processes. Although GPBAR is an important therapeutic target for a spectrum of metabolic and neurodegenerative diseases, its activation has also been found to be linked to carcinogenesis, leading to potential side effects. Here, via functional screening, we found that two specific GPBAR agonists, R399 and INT-777, demonstrated strikingly different regulatory effects on the growth and apoptosis of non–small cell lung cancer (NSCLC) cells both in vitro and in vivo. Further mechanistic investigation showed that R399-induced GPBAR activation displayed an obvious bias for β-arrestin 1 signaling, thus promoting YAP signaling activation to stimulate cell proliferation. Conversely, INT-777 preferentially activated GPBAR-Gs signaling, thus inactivating YAP to inhibit cell proliferation and induce apoptosis. Phosphorylation of GPBAR by GRK2 at S310/S321/S323/S324 sites contributed to R399-induced GPBAR–β-arrestin 1 association. The cryoelectron microscopy (cryo-EM) structure of the R399-bound GPBAR-Gs complex enabled us to identify key interaction residues and pivotal conformational changes in GPBAR responsible for the arrestin signaling bias and cancer cell proliferation. In summary, we demonstrate that different agonists can regulate distinct functions of cell growth and apoptosis through biased GPBAR signaling and control of YAP activity in a NSCLC cell model. The delineated mechanism and structural basis may facilitate the rational design of GPBAR-targeting drugs with both metabolic and anticancer benefits.
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影响因子：
10.5
作者：
Meng Z;Moroishi T;Guan KL
通讯作者：
Guan KL
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
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影响因子：
9.7
作者：
Liu, Xueqing;Chen, Bi;Jiang, Handong
通讯作者：
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DOI：
10.1161/hypertensionaha.113.02043
发表时间：
2014-02
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Bathgate-Siryk A;Dabul S;Pandya K;Walklett K;Rengo G;Cannavo A;De Lucia C;Liccardo D;Gao E;Leosco D;Koch WJ;Lymperopoulos A
通讯作者：
Lymperopoulos A
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH