title: Reversible acetylation regulates vascular endothelial growth factor receptor-2 activity.
abstract: The tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) is a key regulator of angiogenesis. Here we show that VEGFR2 is acetylated in endothelial cells both at four lysine residues forming a dense cluster in the kinase insert domain and at a single lysine located in the receptor activation loop. These modifications are under dynamic control of the acetyltransferase p300 and two deacetylases HDAC5 and HDAC6. We demonstrate that VEGFR2 acetylation essentially regulates receptor phosphorylation. In particular, VEGFR2 acetylation significantly alters the kinetics of receptor phosphorylation after ligand binding, allowing receptor phosphorylation and intracellular signaling upon prolonged stimulation with VEGF. Molecular dynamics simulations indicate that acetylation of the lysine in the activation loop contributes to the transition to an open active state, in which tyrosine phosphorylation is favored by better exposure of the kinase target residues. These findings indicate that post-translational modification by acetylation is a critical mechanism that directly affects VEGFR2 function.
authors.affiliation: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Zecchin
authors.forename: Lucia
authors.initials: L
authors.lastname: Pattarini
authors.forename: Maria Ines
authors.initials: MI
authors.lastname: Gutierrez
authors.forename: Miguel
authors.initials: M
authors.lastname: Mano
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.forename: Mike P
authors.initials: MP
authors.lastname: Myers
authors.forename: Sergio
authors.initials: S
authors.lastname: Pantano
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008024:Ligands; D008239:Lysine / Q000378:metabolism; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D055550:Protein Stability; D017433:Protein Structure, Secondary; D034421:Sus scrofa; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D006655:Histone Deacetylases; D008239:Lysine
keywords: acetylation; angiogenesis; p300; phosphorylation; vascular endothelial growth factor