Active SHP2 protects the pulmonary endothelium through a FAK‐mediated mechanism

Abstract

Enhanced protein tyrosine phosphorylation is associated with increased vascular permeability. We have previously shown that chemical and molecular inhibition of the protein tyrosine phosphatase, SHP2, promotes edema formation in the pulmonary endothelium (EC) in vitro and in vivo; thus implicating SHP2 in a protective role of pulmonary EC barrier function. To study whether this function of SHP2 translates to therapeutic value, we assessed the effect of molecular activation of SHP2 on EC barrier function in response to edemagenic agents, lipopolysaccharide (LPS) and thrombin. Both LPS and thrombin reduced SHP2 activity, which correlated with an elevation in focal adhesion kinase (FAK) Y397 phosphorylation and decrease in SHP2 protein‐protein associations with FAK, p120RasGAP, and p190RhoGAP. In contrast, the barrier protective agent S1P elevated SHP2 activity, enhanced FAK Y576 phosphorylation and increased FAK‐SHP2 association. In vivo, overexpression of constitutively active SHP2 (caSHP2) enhanced EC monolayer resistance at basal conditions and attenuated LPS and thrombin‐induced permeability, however had no effect on s1P‐induced barrier protection. In vivo, overexpression of caSHP2 completely attenuated LPS‐induced pulmonary edema formation. Our data demonstrated that the protective role for SHP2 in maintaining pulmonary EC barrier function may be mediated via FAK.