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Leukemia‐associated Rho guanine‐nucleotide exchange factor is not critical for RhoA regulation, yet is important for platelet activation and thrombosis in mice
Author(s) -
Williams C. M.,
Harper M. T.,
Goggs R.,
Walsh T. G.,
Offermanns S.,
Poole A. W.
Publication year - 2015
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13129
Subject(s) - rhoa , platelet , platelet activation , guanine nucleotide exchange factor , microbiology and biotechnology , thromboxane a2 , thrombin , biology , chemistry , signal transduction , immunology
Summary Background RhoA is an important regulator of platelet responses downstream of Gα 13 , yet we still know little about its regulation in platelets. Leukemia‐associated Rho guanine‐nucleotide exchange factor ( GEF [ LARG ]), a RhoA GEF , 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 the absence of LARG results in a marked reduction in aggregation and dense‐granule secretion in response to the thromboxane mimetic U46619 and proteinase‐activated receptor 4–activating peptide, AYPGKF , but not to adenosine diphosphate. 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 the absence of LARG , although basal activity was reduced, suggesting that LARG may play a housekeeper 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.