A team of G protein subunits have opposing agendas during thrombin-induced increases in lung vessel permeability, show Knezevic and colleagues. Once separated, G
and Gβ
subunits act to open and close, respectively, cell–cell adhesions. The findings implicate the Gβ pathway in deadly disorders causing persistently leaky vessels.
A transient opening of endothelial cell–cell adhesion allows immune cells to infiltrate tissue and fight infection and injury. Thrombin instigates this opening by cleaving the G-protein-coupled PAR1 receptor. Upon subsequent G-protein dissociation, the G subunit initiates RhoA- and MLCK-mediated cell contraction, which pulls apart cell–cell adhesions called adherens junctions, thus creating leaky vessels.
The group’s research now shows that freed Gβ works to undo G’s efforts. By blocking expression of the main endothelial Gβ isoform, Knezevic et al. found that loss of Gβ prevented the resealing of adherens junctions, which typically occurred two to three hours after their opening.
Interaction partners of Gβ that are also known to regulate adherens junctions include Focal Adhesion Kinase (FAK) and the scaffolding protein RACK1. The group had previously shown that FAK suppresses the RhoA cell contraction pathway. They now show that Gβ is required for FAK activation after thrombin exposure.
Without thrombin, Gβ associated with RACK1 in endothelial cells. But with thrombin, the group saw, Gβ left RACK1 and joined FAK and its kinase, Fyn. What controls the system’s timing, such that G undoes junctions well before Gβ rezips them, is not yet clear.
Mice lacking Fyn were unable to turn on FAK and had problems resolving fluid leakage into their lungs upon PAR1 activation. This edema was lessened with the transduction of a version of FAK that mimics its phosphorylation. The findings identify a potential new therapy target for the treatment of acute respiratory distress syndrome (ARDS), which kills tens of thousands of patients in the US every year.
tears and Gβ
repairs
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