PRMT4-mediated arginine methylation promotes tyrosine phosphorylation of VEGFR-2 and regulates filopodia protrusions
Summary: 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...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222010082 |
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| author | Edward Hartsough Rajani R.J. Shelke Razie Amraei Zahra Aryan Saran Lotfollahzadeh Nader Rahimi |
| author_facet | Edward Hartsough Rajani R.J. Shelke Razie Amraei Zahra Aryan Saran Lotfollahzadeh Nader Rahimi |
| author_sort | Edward Hartsough |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-10T20:50:15Z |
| format | Article |
| id | doaj.art-60f4284b6f6942b0bd21267a145216c8 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-10T20:50:15Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-60f4284b6f6942b0bd21267a145216c82022-12-22T01:34:08ZengElsevieriScience2589-00422022-08-01258104736PRMT4-mediated arginine methylation promotes tyrosine phosphorylation of VEGFR-2 and regulates filopodia protrusionsEdward Hartsough0Rajani R.J. Shelke1Razie Amraei2Zahra Aryan3Saran Lotfollahzadeh4Nader Rahimi5Department of Pathology and Laboratory Medicine, Boston University Medical Campus, Boston, MA 02118, USADepartment of Pathology and Laboratory Medicine, Boston University Medical Campus, Boston, MA 02118, USADepartment of Pathology and Laboratory Medicine, Boston University Medical Campus, Boston, MA 02118, USADepartment of Pathology and Laboratory Medicine, Boston University Medical Campus, Boston, MA 02118, USARenal Section, Department of Medicine, Boston University Medical Center, Boston, MA 02118, USADepartment of Pathology and Laboratory Medicine, Boston University Medical Campus, Boston, MA 02118, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004222010082BiochemistryMolecular physiologyCell biology |
| spellingShingle | Edward Hartsough Rajani R.J. Shelke Razie Amraei Zahra Aryan Saran Lotfollahzadeh Nader Rahimi PRMT4-mediated arginine methylation promotes tyrosine phosphorylation of VEGFR-2 and regulates filopodia protrusions iScience Biochemistry Molecular physiology Cell biology |
| title | PRMT4-mediated arginine methylation promotes tyrosine phosphorylation of VEGFR-2 and regulates filopodia protrusions |
| title_full | PRMT4-mediated arginine methylation promotes tyrosine phosphorylation of VEGFR-2 and regulates filopodia protrusions |
| title_fullStr | PRMT4-mediated arginine methylation promotes tyrosine phosphorylation of VEGFR-2 and regulates filopodia protrusions |
| title_full_unstemmed | PRMT4-mediated arginine methylation promotes tyrosine phosphorylation of VEGFR-2 and regulates filopodia protrusions |
| title_short | PRMT4-mediated arginine methylation promotes tyrosine phosphorylation of VEGFR-2 and regulates filopodia protrusions |
| title_sort | prmt4 mediated arginine methylation promotes tyrosine phosphorylation of vegfr 2 and regulates filopodia protrusions |
| topic | Biochemistry Molecular physiology Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222010082 |
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