Reversible acetylation regulates vascular endothelial growth factor receptor-2 activity

TY - JOUR

T1 - Reversible acetylation regulates vascular endothelial growth factor receptor-2 activity

AU - Zecchin, Annalisa

AU - Pattarini, Lucia

AU - Gutierrez, Maria Ines

AU - Mano, Miguel

AU - Mai, Antonello

AU - Valente, Sergio

AU - Myers, Mike P.

AU - Pantano, Sergio

AU - Giacca, Mauro

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - acetylation

KW - angiogenesis

KW - p300

KW - phosphorylation

KW - vascular endothelial growth factor

UR - http://www.scopus.com/inward/record.url?scp=84899675551&partnerID=8YFLogxK

U2 - 10.1093/jmcb/mju010

DO - 10.1093/jmcb/mju010

M3 - Article

C2 - 24620033

AN - SCOPUS:84899675551

SN - 1674-2788

VL - 6

SP - 116

EP - 127

JO - Journal of Molecular Cell Biology

JF - Journal of Molecular Cell Biology

IS - 2

ER -