Role of Protein Tyrosine Phosphatase Receptor, Type Gamma (PTPRG) in the regulation of endothelial permeability.

The vascular endothelium is a selective barrier that regulates, through paracellular and/or transcellular routes, the transport of macro-molecules and cells across the vessels. Modifications of endothelial cell barrier permeability are involved in many physio-pathological events, such as acute inflammatory response and cancer. Several signalling molecules regulate endothelial permeability, regulating actin cytoskeleton dynamics and/or junctional complex disassembly. Although the role of protein kinases in the regulation of endothelial permeability during physio-pathological conditions is well established, the involvement of protein phosphatases in endothelial cells function still remains poorly defined. In a recent study, our laboratory showed that the Protein Tyrosine Phosphatase Receptor, type gamma (PTPRG), which belongs to the protein tyrosine phosphatases receptor-like family, has a negative role on the regulation of recruitment of human primary monocytes. Indeed, activation of PTPRG tyr-phosphatase activity by means of two Trojan fusion proteins, namely TAT-ICD, that encompasses the complete intracellular active enzymatic domain of PTPRG, and P1-WD (P1-wedge domain), which activates the endogenous PTPRG activity, inhibits signalling pathways controlling integrin activation by chemoattractants. In this study, by taking advantage of TAT-ICD and P1-WD, we investigated the role of PTPRG in the regulation of endothelial permeability. We provided evidence showing that PTPRG activation induces a time- and dose-dependent increase of permeability of endothelial cell monolayers. To corroborate these data, we evaluated the function of ZO-1, a tight junction-associated protein. The data indicated a dose-dependent reduction of ZO-1 expression upon PTPRG activation. Since ZO-1 protein expression critically regulates the stability of tight junctions, these data support the role of PTPRG in the regulation of endothelial permeability. We speculated that PTPRG activity may modulate, directly or indirectly, the phosphorylation state of signalling events controlling the expression and function of junctional proteins involved in the control of endothelial permeability.