Mislocalization of protein kinase A drives pathology in Cushing's syndrome.
Mislocalization of protein kinase A drives pathology in Cushing's syndrome.
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蛋白激酶A的错误定位驱动了库欣综合征的病理
DOI：
10.1016/j.celrep.2022.111073
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发表时间：
2022-07-12
期刊：
影响因子：
8.8
通讯作者：
Scott, John D.
中科院分区：
文献类型：
--
作者：
Omar, Mitchell H.;Byrne, Dominic P.;Jones, Kiana N.;Lakey, Tyler M.;Collins, Kerrie B.;Lee, Kyung-Soon;Daly, Leonard A.;Forbush, Katherine A.;Lau, Ho-Tak;Golkowski, Martin;McKnight, G. Stanley;Breault, David T.;Lefrancois-Martinez, Anne-Marie;Martinez, Antoine;Eyers, Claire E.;Baird, Geoffrey S.;Ong, Shao-En;Smith, F. Donelson;Eyers, Patrick A.;Scott, John D.
蛋白激酶A（PKAc）催化亚基的突变导致应激激素紊乱肾上腺库欣综合征。我们定义了PKAc-L205 R和W196 R变体的作用机制。邻近蛋白质组学技术表明，这两个库欣的突变体被排除在A激酶锚定蛋白（AKAP）信号岛，而活细胞光活化显微镜显示，这些激酶突变体不加区别地扩散到整个细胞。只有从AKAP中取代天然PKAc的cAMP类似物药物才能增强皮质醇的释放。将PKAc突变体整合到AKAP复合物中的拯救实验消除了皮质醇的过度产生，表明激酶锚定恢复了正常的内分泌功能。对肾上腺特异性PKAc-W196 R敲入小鼠和库欣综合征患者组织的分析揭示了该疾病的缺陷信号传导机制。令人惊讶的是，每个库欣氏突变体参与不同的促有丝分裂信号传导途径，PKAc-L205 R上调雅普/TAZ，PKAc-W196 R激活ERK激酶。因此，每个库欣变异体的异常时空调节促进不同下游致病信号的传递。蛋白激酶A（PKAc）催化亚基的突变会导致一种称为肾上腺库欣综合征的应激激素紊乱。Omar等人发现错误定位是muplatin激酶病理学的必要组成部分。值得注意的是，两种看似相似的致病PKAc变体在亚细胞定位、生理化学性质和下游信号通路方面存在分歧。
Mutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushing’s syndrome. We define mechanisms of action for the PKAc-L205R and W196R variants. Proximity proteomic techniques demonstrate that both Cushing’s mutants are excluded from A kinase-anchoring protein (AKAP)-signaling islands, whereas live-cell photoactivation microscopy reveals that these kinase mutants indiscriminately diffuse throughout the cell. Only cAMP analog drugs that displace native PKAc from AKAPs enhance cortisol release. Rescue experiments that incorporate PKAc mutants into AKAP complexes abolish cortisol overproduction, indicating that kinase anchoring restores normal endocrine function. Analyses of adrenal-specific PKAc-W196R knockin mice and Cushing’s syndrome patient tissue reveal defective signaling mechanisms of the disease. Surprisingly each Cushing’s mutant engages a different mitogenic-signaling pathway, with upregulation of YAP/TAZ by PKAc-L205R and ERK kinase activation by PKAc-W196R. Thus, aberrant spatiotemporal regulation of each Cushing’s variant promotes the transmission of distinct downstream pathogenic signals. Mutations in the catalytic subunit of protein kinase A (PKAc) cause a stress hormone disorder called adrenal Cushing’s syndrome. Omar et al. uncover mislocalization as a required component of mutant-kinase pathology. Remarkably, two seemingly similar disease-causing PKAc variants diverge in subcellular localization, physiochemical properties, and downstream signaling pathways.
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