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Uncovering kappa-opioid receptor agonist-induced PAK1/2 phosphorylation by quantitative phosphoproteomics

Wu, Jianhong, Jiang, Qinghui, Zhu, Hongwen, Zhou, Yanting, Lu, Dayun, Liu, Xing, Chen, Xiangling, Chen, Jie, Wang, Yujun, Liu, Jinggen, Song, Rentao, Huang, Ruimin, Zhou, Hu
Biochemical and biophysical research communications 2019 v.516 no.1 pp. 320-326
G-protein coupled receptors, actin, agonists, cognition, cytoskeleton, diuresis, immune system, ligands, neurons, nociception, phosphorylation, phosphotransferases (kinases), prediction, proteomics, signal transduction, therapeutics
Kappa-opioid receptor (KOR) is a member of G-protein coupled receptors (GPCRs) expressed in serotonergic neurons and neuronal terminals. The involvement of KOR ligands in nociception, diuresis, emotion, cognition, and immune system has been extensively studied. Omics-based methods are preferable to understand the signaling cascade after KOR activation in a systematic manner. In this study, an in-depth quantitative phosphoproteomic analysis resulted in 305 phosphosites, which were significantly changed in three KOR-overexpressed cells upon treatment with two KOR agonists. The subsequent substrate-kinase prediction analysis revealed that 18 potential kinases might be activated under stimulation of the agonists. We found that phosphorylation of PAK1/2 (p21-activated kinase 1/2) was induced by KOR agonists, resulting in reduced actin stress fibers and cytoskeletal reorganization. In summary, this quantitative phosphoproteomics-based research studied the downstream phosphorylation events upon KOR activation, which may shed light on the investigations of KOR signaling pathway and targeted therapy for KOR-related diseases.