Abstract
Mast cells are key participants in allergic diseases via activation of high-affinity IgE receptors (FcepsilonRI) 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, W(sh)/W(sh) 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 FcepsilonRI-induced degranulation. Further, Pak1(-/-) BMMCs demonstrated diminished calcium mobilization and altered depolymerization of cortical filamentous actin (F-actin) in response to FcepsilonRI stimulation. These data implicate Pak1 as an essential molecular target for modulating acute mast cell responses that contribute to allergic diseases.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Actins / metabolism
-
Adoptive Transfer
-
Animals
-
Antigens, CD / genetics
-
Antigens, CD / physiology
-
Biological Transport
-
Biopolymers
-
Bone Marrow Cells / cytology
-
Calcimycin / pharmacology
-
Calcium Signaling / drug effects
-
Calcium Signaling / physiology*
-
Cytoskeleton / metabolism
-
Cytoskeleton / ultrastructure*
-
Enzyme Activation
-
Female
-
Immunoglobulin E / immunology
-
Mast Cells / metabolism*
-
Membrane Glycoproteins / genetics
-
Membrane Glycoproteins / physiology
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
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
-
beta-N-Acetylhexosaminidases / metabolism
-
p21-Activated Kinases / deficiency
-
p21-Activated Kinases / genetics
-
p21-Activated Kinases / physiology*
Substances
-
Actins
-
Antigens, CD
-
Biopolymers
-
Cd63 protein, mouse
-
Membrane Glycoproteins
-
Platelet Membrane Glycoproteins
-
Receptors, IgE
-
Recombinant Fusion Proteins
-
Tetraspanin 30
-
Immunoglobulin E
-
Calcimycin
-
Pak1 protein, mouse
-
p21-Activated Kinases
-
beta-N-Acetylhexosaminidases