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C3G contributes to platelet activation and aggregation by regulating major signaling pathways

signal Transduction and Targeted Therapy 2020年第1期5卷 2103-2117页

作者： sara Gutiérrez-Herrero Cristina Fernández-Infante Luis Hernández-Cano sara Ortiz-Rivero Carlos Guijas Víctor Martín-Granado JoséRamón González-Porras jesús balsinde Almudena Porras Carmen Guerrero Instituto de Biología Molecular y Celular del Cáncer(IMBCC) University of Salamanca-CSICSalamancaSpain Instituto de Investigación Biomédica de salamanca(IBsAL) SalamancaSpain Instituto de Biología y Genética Molecular(IBGM) Consejo Superior de Investigaciones Científicas(CSIC)University of ValladolidValladolidSpain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas(CIBERDEM) MadridSpain Departamento de Hematologiá Hospital Universitario de Salamanca(HUS)SalamancaSpain Departamento de Bioquímica y Biología Molecular Facultad de FarmaciaComplutense University of Madrid.Instituto de Investigación Sanitaria del Hospital Clínico San Carlos(IdISSC)MadridSpain Departamento de Medicina University of SalamancaSalamancaSpain

C3G is a GEF(guanine nucleotide exchange factor)for Rap GTPases,among which the isoform Rap1b is an essential protein in platelet *** transgenic mouse models with platelet-specific overexpression of C3G or mutant C3GΔCat,we have unveiled a new function of C3G in regulating the hemostatic function of platelets through its participation in the thrombin-PKCRap1b pathway.C3G also plays important roles in angiogenesis,tumor growth,and metastasis through its regulation of the platelet *** addition,C3G contributes to megakaryopoiesis and ***,we used a platelet-specific C3G-KO mouse model to further support the role of C3G in hemostasis.C3G-KO platelets showed a significant delay in platelet activation and aggregation as a consequence of the defective activation of Rap1,which resulted in decreased thrombus formation in ***,we explored the contribution of C3G-Rap1b to platelet signaling pathways triggered by thrombin,PMA or ADP,in the referenced transgenic mouse model,through the use of a battery of specific *** found that platelet C3G is phosphorylated at Tyr504 by a mechanism involving *** phosphorylation was shown to be positively regulated by ERKs through their inhibition of the tyrosine phosphatase ***,C3G participates in the ADP-P2Y12-PI3K-Rap1b pathway and is a mediator of thrombin-TXA2 ***,it inhibits the synthesis of TXA2 through cPLA2 *** together,our data reveal the critical role of C3G in the main pathways leading to platelet activation and aggregation through the regulation of Rap1b.

关键词： C3G platelet activation

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