Leukemia-associated Rho guanine-nucleotide exchange factor is not critical for RhoA regulation, yet is important for platelet activation and thrombosis in mice

Background: RhoA is an important regulator of platelet responses downstream of Gα₁₃, yet we still know little about its regulation in platelets. Leukemia-Associated RhoGEF (LAR6G), a RhoAGEF, is highly expressed in platelets and may constitute a major upstream activator of RhoA. To this end, it is important to determine the role of LARG in platelet function and thrombosis.

Methods and Results: Using a platelet-specific gene knockout, we show that absence of LARG results in a marked reduction in aggregation and dense-granule secretion in response to the thromboxane mimetic, U46619, and PAR4-activating peptide, AYPGKF, but not to ADP. In a ferric chloride thrombosis model in vivo, this translated into a defect, under mild injury conditions. Importantly, agonist-induced RhoA activation was not affected by absence of LARG, although basal activity was reduced, suggesting that LARG may play a house-keeper role in regulating constitutive RhoA activity.

Conclusions:LARG plays an important role in platelet function and thrombosis in vivo. However, although LARG may have a role in regulating the resting activation state of RhoA, its role in regulating platelet function may principally be through RhoA-independent pathways, possibly through other Rho-family members.