Smoothened transduces Hedgehog signals via activity-dependent sequestration of PKA catalytic subunits
Smoothened transduces Hedgehog signals via activity-dependent sequestration of PKA catalytic subunits
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DOI：
10.1101/2020.07.01.183079
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发表时间：
2020-07
期刊：
影响因子：
9.8
通讯作者：
Corvin D. Arveseth;John T. Happ;Danielle S. Hedeen;Ju‐Fen Zhu;Jacob L. Capener;Dana K. Shaw;I. Deshpande;Jiahao Liang;Jiewei Xu;Sara L. Stubben;Isaac B. Nelson;Madison F. Walker;N. Krogan;D. Grunwald;Ruth Hüttenhain;A. Manglik;Benjamin R. Myers
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作者：
Corvin D. Arveseth;John T. Happ;Danielle S. Hedeen;Ju‐Fen Zhu;Jacob L. Capener;Dana K. Shaw;I. Deshpande;Jiahao Liang;Jiewei Xu;Sara L. Stubben;Isaac B. Nelson;Madison F. Walker;N. Krogan;D. Grunwald;Ruth Hüttenhain;A. Manglik;Benjamin R. Myers
Hedgehog （Hh）通路对器官发育、体内平衡和再生至关重要。这个级联的功能障碍导致了几种癌症。为了控制通路靶基因的表达，G蛋白偶联受体（GPCR） Smoothened （SMO）通过一种未知的机制激活胶质瘤相关（GLI）转录因子。在这里，我们表明，SMO通过结合和隔离膜上的蛋白激酶A （PKA）催化亚基来激活GLI，而不是符合传统的GPCR信号范式。这种隔离是由GPCR激酶2 （GRK2）介导的SMO胞内结构域磷酸化引发的，可以阻止PKA磷酸化可溶性底物，从而将GLI从PKA介导的抑制中释放出来。我们的工作提供了一种直接将膜上的Hh信号转导与细胞核中的GLI转录联系起来的机制。这一过程在物种之间比普遍的假设更基本地相似。这里描述的机制可能广泛适用于其他GPCR和pka级联在不同的生物学领域。
The Hedgehog (Hh) pathway is essential for organ development, homeostasis, and regeneration. Dysfunction of this cascade drives several cancers. To control expression of pathway target genes, the G protein-coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase 2 (GRK2)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking Hh signal transduction at the membrane to GLI transcription in the nucleus. This process is more fundamentally similar between species than prevailing hypotheses suggest. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades in diverse areas of biology.