Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Nagoya 466-8550, Japan.
Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Japan.
Cells. 2021 Dec 24;11(1):47. doi: 10.3390/cells11010047.
Protein phosphorylation plays critical roles in a variety of intracellular signaling pathways and physiological functions that are controlled by neurotransmitters and neuromodulators in the brain. Dysregulation of these signaling pathways has been implicated in neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder and schizophrenia. While recent advances in mass spectrometry-based proteomics have allowed us to identify approximately 280,000 phosphorylation sites, it remains largely unknown which sites are phosphorylated by which kinases. To overcome this issue, previously, we developed methods for comprehensive screening of the target substrates of given kinases, such as PKA and Rho-kinase, upon stimulation by extracellular signals and identified many candidate substrates for specific kinases and their phosphorylation sites. Here, we developed a novel online database to provide information about the phosphorylation signals identified by our methods, as well as those previously reported in the literature. The "KANPHOS" (Kinase-Associated Neural Phospho-Signaling) database and its web portal were built based on a next-generation XooNIps neuroinformatics tool. To explore the functionality of the KANPHOS database, we obtained phosphoproteomics data for adenosine-A2A-receptor signaling and its downstream MAPK-mediated signaling in the striatum/nucleus accumbens, registered them in KANPHOS, and analyzed the related pathways.
蛋白质磷酸化在各种细胞内信号通路和生理功能中发挥着关键作用,这些信号通路和生理功能受大脑中的神经递质和神经调质的控制。这些信号通路的失调与神经发育障碍有关,包括自闭症谱系障碍、注意缺陷多动障碍和精神分裂症。虽然基于质谱的蛋白质组学的最新进展使我们能够鉴定出大约 280000 个磷酸化位点,但仍然不清楚哪些位点是由哪些激酶磷酸化的。为了解决这个问题,我们之前开发了综合筛选特定激酶(如 PKA 和 Rho-激酶)的靶底物的方法,这些靶底物在外源信号刺激下被鉴定出来,确定了许多特定激酶及其磷酸化位点的候选底物。在这里,我们开发了一个新的在线数据库,提供了我们的方法所鉴定的磷酸化信号以及文献中以前报道的磷酸化信号的信息。“KANPHOS”(激酶相关神经磷酸化信号)数据库及其网络门户是基于下一代 XooNIps 神经信息学工具构建的。为了探索 KANPHOS 数据库的功能,我们获得了腺苷 A2A 受体信号及其在纹状体/伏隔核中的下游 MAPK 介导信号的磷酸蛋白质组学数据,将其注册到 KANPHOS 中,并分析了相关途径。
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