Figure 7.

Scheme of the proposed molecular mechanism. Neddylated Cullin 3 (CUL3) regulates vascular endothelial (VE)‐cadherin turnover in endothelial cells. Under normal conditions, neddylated CUL3 complex constitutively degrades unidentified VE‐cadherin destabilizing factor(s) through a ubiquitin (ub)–proteasome system, thereby stabilizing endothelial barrier integrity by maintaining a high level of VE‐cadherin protein. Following treatment with a NEDD8‐activating enzyme inhibitor, MLN4924 or CUL3 siRNA, VE‐cadherin is depleted in the cells because of the accumulation of VE‐cadherin destabilizing factor(s). Consequently, endothelial vascular permeability is increased. Gray arrows denote vascular leakage.