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标题：PRMT4-mediated arginine methylation promotes tyrosine phosphorylation of VEGFR-2 and regulates filopodia protrusions
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作者：Edward Hartsough ; Rajani R.J. Shelke ; Razie Amraei 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：8
页码：1-14
DOI：10.1016/j.isci.2022.104736
语种：English
出版社：Elsevier
摘要：SummaryThrough tightly controlled multilayer mechanisms, vascular endothelial growth factor receptor-2 (VEGFR-2) activation and its downstream signal transduction govern vasculogenesis and pathological angiogenesis, such as tumor angiogenesis. Therefore, it is critical to understand the molecular mechanisms governing VEGFR-2 signal transduction. We report that protein arginine methyltransferase 4 (PRMT4) via its highly conserved EVH1 and PH domain-like N-terminal domain binds to VEGFR-2 and mediates methylation of the juxtamembrane arginine 817 (R817) on VEGFR-2. Methylation of R817 selectively increases phosphorylation of tyrosine 820 (Y820). Phosphorylation of Y820 facilitates the c-Src binding with VEGFR-2 via Src homology domain 2 (SH2). Interfering with the methylation of R817 or phosphorylation of Y820 inhibits VEGFR-2-induced filopodia protrusions, a process that is critical for the core angiogenic responses of VEGFR-2. Methylation of R817 is an important previously unrecognized mechanism of the angiogenic signaling of VEGFR-2, with implications for the development of novel-targeted VEGFR-2 inhibitors.Graphical abstractDisplay OmittedHighlights•Arginine 817 methylation regulates phosphorylation of Y820 on VEGFR-2•Phosphorylation of Y820 recruits c-Src kinase to VEGFR-2, leading to its activation•VEGFR-2/c-Src axis mediates filopodia protrusions in endothelial cellsBiochemistry; Molecular physiology; Cell biology