Opposing Roles of GSK3α and GSK3β Phosphorylation in Platelet Function and Thrombosis

One of the mechanisms by which PI3 kinase can regulate platelet function is through phosphorylation of downstream substrates, including glycogen synthase kinase-3 (GSK3)alpha and GSK3 beta. Platelet activation results in the phosphorylation of an N-terminal serine residue in GSK3 alpha (Ser21) and GSK3 beta (Ser9), which competitively inhibits substrate phosphorylation. However, the role of phosphorylation of these paralogs is still largely unknown. Here, we employed GSK3 alpha/beta phosphorylation-resistant mouse models to explore the role of this inhibitory phosphorylation in regulating platelet activation. Expression of phosphorylation-resistant GSK3 alpha/beta reduced thrombin-mediated platelet aggregation, integrin alpha(IIb)beta(3) activation, and alpha-granule secretion, whereas platelet responses to the GPVI agonist collagen-related peptide (CRP-XL) were significantly enhanced. GSK3 single knock-in lines revealed that this divergence is due to differential roles of GSK3 alpha and GSK3 beta phosphorylation in regulating platelet function. Expression of phosphorylation-resistant GSK3 alpha resulted in enhanced GPVI-mediated platelet activation, whereas expression of phosphorylation-resistant GSK3 beta resulted in a reduction in PAR-mediated platelet activation and impaired in vitro thrombus formation under flow. Interestingly, the latter was normalised in double GSK3 alpha/beta KI mice, indicating that GSK3 alpha KI can compensate for the impairment in thrombosis caused by GSK3 beta KI. In conclusion, our data indicate that GSK3 alpha and GSK3 beta have differential roles in regulating platelet function.

Automated summary

Phosphorylation-resistant GSK3 alpha/beta expression affects platelet activation, with differential roles of GSK3 alpha and GSK3 beta phosphorylation in regulating platelet function.