p21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics

Mast cells are key participants in allergic diseases via activation of high-affinity IgE receptors (FcϵRI) resulting in release of proinflammatory mediators. The biochemical pathways linking IgE activation to calcium influx and cytoskeletal changes required for intracellular granule release are inco...

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Bibliographic Details
Published in:	Blood 2009-03, Vol.113 (12), p.2695-2705
Main Authors:	Allen, Jayme D., Jaffer, Zahara M., Park, Su-Jung, Burgin, Sarah, Hofmann, Clemens, Sells, Mary Ann, Chen, Shi, Derr-Yellin, Ethel, Michels, Elizabeth G., McDaniel, Andrew, Bessler, Waylan K., Ingram, David A., Atkinson, Simon J., Travers, Jeffrey B., Chernoff, Jonathan, Clapp, D. Wade
Format:	Article
Language:	eng
Subjects:	Actins - metabolism Adoptive Transfer Animals Antigens, CD - genetics Antigens, CD - physiology beta-N-Acetylhexosaminidases - metabolism Biological and medical sciences Biological Transport Biopolymers Bone Marrow Cells - cytology Calcimycin - pharmacology Calcium Signaling - drug effects Calcium Signaling - physiology Cytoskeleton - metabolism Cytoskeleton - ultrastructure Enzyme Activation Female Hematologic and hematopoietic diseases Immunobiology Immunoglobulin E - immunology Mast Cells - metabolism Medical sciences Membrane Glycoproteins - genetics Membrane Glycoproteins - physiology Mice Mice, Inbred C57BL Mice, Knockout p21-Activated Kinases - deficiency p21-Activated Kinases - genetics p21-Activated Kinases - physiology Passive Cutaneous Anaphylaxis - immunology Platelet Membrane Glycoproteins Radiation Chimera Receptors, IgE - physiology Recombinant Fusion Proteins - physiology Secretory Vesicles - drug effects Secretory Vesicles - metabolism Signal Transduction Tetraspanin 30
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Summary:	Mast cells are key participants in allergic diseases via activation of high-affinity IgE receptors (FcϵRI) resulting in release of proinflammatory mediators. The biochemical pathways linking IgE activation to calcium influx and cytoskeletal changes required for intracellular granule release are incompletely understood. We demonstrate, genetically, that Pak1 is required for this process. In a passive cutaneous anaphylaxis experiment, Wsh/Wsh mast cell–deficient mice locally reconstituted with Pak1−/− bone marrow–derived mast cells (BMMCs) experienced strikingly decreased allergen-induced vascular permeability compared with controls. Consistent with the in vivo phenotype, Pak1−/− BMMCs exhibited a reduction in FcϵRI-induced degranulation. Further, Pak1−/− BMMCs demonstrated diminished calcium mobilization and altered depolymerization of cortical filamentous actin (F-actin) in response to FcϵRI stimulation. These data implicate Pak1 as an essential molecular target for modulating acute mast cell responses that contribute to allergic diseases.
ISSN:	0006-4971 1528-0020