Figure 7. Model for the role of the Abl family kinases in signaling pathways regulating endothelial permeability.

The Abl and Arg kinases are activated in endothelial cells downstream of receptors for the permeability-inducing factors VEGF, thrombin, and histamine. VEGF-mediated Abl kinase activation requires Src family kinase activity. The Abl kinases positively regulate phosphorylation of MLC2 (S19) in response to these permeability-inducing agonists, likely through regulating the activity of Ca²⁺/calmodulin-dependent targets such as MLCK. Abl kinase activity is required for maximal Ca²⁺ mobilization in response to stimulation with permeability-inducing factors. The Abl kinases additionally modulate VEGF-induced phosphorylation of VEGFR2 at Y1175, which regulates downstream PLCγ activation, IP₃ generation, and ER Ca²⁺ release. Abl kinases promote Ca²⁺ mobilization by thrombin and histamine by mechanisms yet to be characterized. Abl kinases negatively regulate basal activity levels of the Rac1 and Rap1 GTPases, which have been shown to support endothelial barrier function by promoting cortical actin deposition and adherens junction stability. Abbreviations: EC, endothelial cell; VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2; Y, tyrosine; PAR-1, protease-activated receptor 1 (thrombin); H1, histamine H1 receptor; MLC2, myosin regulatory light chain; S, serine; MLCK, myosin light chain kinase; PLC, phospholipase C; IP₃, inositol-1,4,5-trisphosphate; IP₃R, IP₃ receptor; ER, endoplasmic reticulum.