Lysine methylation promotes VEGFR-2 activation and angiogenesis
- Authors
- Hartsough, E.J., Meyer, R.D., Chitalia, V., Jiang, Y., Marquez, V.E., Zhdanova, I.V., Weinberg, J., Costello, C.E., and Rahimi, N.
- ID
- ZDB-PUB-140123-28
- Date
- 2013
- Source
- Science signaling 6(304): ra104 (Journal)
- Registered Authors
- Zhdanova, Irina
- Keywords
- none
- MeSH Terms
-
- Neoplasms/genetics
- Neoplasms/metabolism*
- Neoplasms/pathology
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism*
- Zebrafish/genetics
- Zebrafish/metabolism*
- Humans
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Cell Line, Tumor
- Mice
- Neoplasm Transplantation
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism*
- Neovascularization, Pathologic/pathology
- Heterografts
- HEK293 Cells
- Lysine/genetics
- Lysine/metabolism*
- Methylation
- Vascular Endothelial Growth Factor Receptor-2
- Protein Processing, Post-Translational*
- Animals
- PubMed
- 24300896 Full text @ Sci. Signal.
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 Lys1041, 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 Lys1041 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 Lys1041 was required for VEGFR-2?mediated angiogenesis in zebrafish and tumor growth in mice. We propose that methylation of Lys1041 promotes the activation of VEGFR-2 and that similar posttranslational modification could also regulate the activity of other receptor tyrosine kinases.