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http://purl.uniprot.org/citations/36804596http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/36804596http://www.w3.org/2000/01/rdf-schema#comment"

Background

Drug-induced anaphylaxis is triggered by the direct stimulation of mast cells (MCs) via Mas-related G protein-coupled receptor X2 (MRGPRX2; mouse ortholog MRGPRB2). However, the precise mechanism that links MRGPRX2/B2 to MC degranulation is poorly understood. Dedicator of cytokinesis 2 (DOCK2) is a Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 regulates migration and activation of leukocytes, its role in MCs remains unknown.

Objective

We aimed to elucidate whether-and if so, how-DOCK2 is involved in MRGPRX2/B2-mediated MC degranulation and anaphylaxis.

Methods

Induction of drug-induced systemic and cutaneous anaphylaxis was compared between wild-type and DOCK2-deficient mice. In addition, genetic or pharmacologic inactivation of DOCK2 in human and murine MCs was used to reveal its role in MRGPRX2/B2-mediated signal transduction and degranulation.

Results

Induction of MC degranulation and anaphylaxis by compound 48/80 and ciprofloxacin was severely attenuated in the absence of DOCK2. Although calcium influx and phosphorylation of several signaling molecules were unaffected, MRGPRB2-mediated Rac activation and phosphorylation of p21-activated kinase 1 (PAK1) were impaired in DOCK2-deficient MCs. Similar results were obtained when mice or MCs were treated with small-molecule inhibitors that bind to the catalytic domain of DOCK2 and inhibit Rac activation.

Conclusion

DOCK2 regulates MRGPRX2/B2-mediated MC degranulation through Rac activation and PAK1 phosphorylation, thereby indicating that the DOCK2-Rac-PAK1 axis could be a target for preventing drug-induced anaphylaxis."xsd:string
http://purl.uniprot.org/citations/36804596http://purl.org/dc/terms/identifier"doi:10.1016/j.jaci.2023.01.029"xsd:string
http://purl.uniprot.org/citations/36804596http://purl.uniprot.org/core/author"Fukui Y."xsd:string
http://purl.uniprot.org/citations/36804596http://purl.uniprot.org/core/author"Matsubara K."xsd:string
http://purl.uniprot.org/citations/36804596http://purl.uniprot.org/core/author"Morino K."xsd:string
http://purl.uniprot.org/citations/36804596http://purl.uniprot.org/core/author"Hirotani K."xsd:string
http://purl.uniprot.org/citations/36804596http://purl.uniprot.org/core/author"Uruno T."xsd:string
http://purl.uniprot.org/citations/36804596http://purl.uniprot.org/core/author"Sakata D."xsd:string
http://purl.uniprot.org/citations/36804596http://purl.uniprot.org/core/author"Akiyoshi S."xsd:string
http://purl.uniprot.org/citations/36804596http://purl.uniprot.org/core/author"Kunimura K."xsd:string
http://purl.uniprot.org/citations/36804596http://purl.uniprot.org/core/date"2023"xsd:gYear
http://purl.uniprot.org/citations/36804596http://purl.uniprot.org/core/name"J Allergy Clin Immunol"xsd:string
http://purl.uniprot.org/citations/36804596http://purl.uniprot.org/core/pages"1585-1594.e9"xsd:string
http://purl.uniprot.org/citations/36804596http://purl.uniprot.org/core/title"DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation and drug-induced anaphylaxis."xsd:string
http://purl.uniprot.org/citations/36804596http://purl.uniprot.org/core/volume"151"xsd:string
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