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Reversible acetylation regulates vascular endothelial growth factor receptor-2 activity

2014; Oxford University Press; Volume: 6; Issue: 2 Linguagem: Inglês

10.1093/jmcb/mju010

1674-2788

Annalisa Zecchin, Lucia Pattarini, María Inés Gutiérrez, Miguel Mano, Antonello Mai, Sérgio Valente, Mike Myers, Sergio Pantano, Mauro Giacca,

Ubiquitin and proteasome pathways

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.