期刊
ISCIENCE
卷 25, 期 8, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2022.104736
关键词
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资金
- Boston University School of Medicine Genome Science Institute, Boston University
Activation and signal transduction of vascular endothelial growth factor receptor-2 (VEGFR-2) play crucial roles in vasculogenesis and pathological angiogenesis. The study reveals that protein arginine methyltransferase 4 (PRMT4) mediates methylation of a specific site on VEGFR-2, which affects VEGFR-2-induced angiogenic responses. This finding may have implications for the development of targeted VEGFR-2 inhibitors.
Through 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.
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