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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook 2016     Display Documents



ID: 723905.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook 2016
Leukemia-associated Rho guanine-nucleotide exchange factor is not critical for RhoA regulation, yet is important for platelet activation and thrombosis in mice
Authors:Williams, C. M.; Harper, M. T.; Goggs, R.; Walsh, T. G.; Offermanns, S.; Poole, A. W.
Date of Publication (YYYY-MM-DD):2015-11
Title of Journal:J Thromb Haemost
Volume:13
Issue / Number:11
Start Page:2102
End Page:2107
Audience:Not Specified
Abstract / Description:BACKGROUND: RhoA is an important regulator of platelet responses downstream of Galpha13 , 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.
Free Keywords:Larg protein, mouse; RhoA protein, mouse; gene knockout; mouse; platelets; thrombosis
External Publication Status:published
Document Type:Article
Communicated by:n.n.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
Identifiers:ISSN:1538-7836 (Electronic) 1538-7836 (Linking) %R 10.1111/jth.13129
URL:http://www.ncbi.nlm.nih.gov/pubmed/26334261
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