title: Lysine methylation promotes VEGFR-2 activation and angiogenesis.
abstract: Activation of vascular endothelial growth factor receptor-2 (VEGFR-2), an endothelial cell receptor tyrosine kinase, promotes tumor angiogenesis and ocular neovascularization. We report the methylation of VEGFR-2 at multiple Lys and Arg residues, including Lys(1041), a residue that is proximal to the activation loop of the kinase domain. Methylation of VEGFR-2 was independent of ligand binding and was not regulated by ligand stimulation. Methylation of Lys(1041) enhanced tyrosine phosphorylation and kinase activity in response to ligands. Additionally, interfering with the methylation of VEGFR-2 by pharmacological inhibition or by site-directed mutagenesis revealed that methylation of Lys(1041) was required for VEGFR-2-mediated angiogenesis in zebrafish and tumor growth in mice. We propose that methylation of Lys(1041) promotes the activation of VEGFR-2 and that similar posttranslational modification could also regulate the activity of other receptor tyrosine kinases.
authors.affiliation: 1Departments of Pathology and Ophthalmology, School of Medicine, Boston University Medical Campus, Boston, MA 02118, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hartsough
authors.forename: Rosana D
authors.initials: RD
authors.lastname: Meyer
authors.forename: Vipul
authors.initials: V
authors.lastname: Chitalia
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Irina V
authors.initials: IV
authors.lastname: Zhdanova
authors.forename: Janice
authors.initials: J
authors.lastname: Weinberg
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Costello
authors.forename: Nader
authors.initials: N
authors.lastname: Rahimi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D040301:Vascular Endothelial Growth Factor Receptor-2; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D029961:Zebrafish Proteins; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D008239:Lysine