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 (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.
Allen
Jayme D
JD
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Jaffer
Zahara M
ZM
Park
Su-Jung
SJ
Burgin
Sarah
S
Hofmann
Clemens
C
Sells
Mary Ann
MA
Chen
Shi
S
Derr-Yellin
Ethel
E
Michels
Elizabeth G
EG
McDaniel
Andrew
A
Bessler
Waylan K
WK
Ingram
David A
DA
Atkinson
Simon J
SJ
Travers
Jeffrey B
JB
Chernoff
Jonathan
J
Clapp
D Wade
DW
D000199:Actins / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001692:Biological Transport; D001704:Biopolymers; D001854:Bone Marrow Cells / Q000166:cytology; D000001:Calcimycin / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure*; D004789:Enzyme Activation; D005260:Female; D007073:Immunoglobulin E / Q000276:immunology; D008407:Mast Cells / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010323:Passive Cutaneous Anaphylaxis / Q000276:immunology; D010980:Platelet Membrane Glycoproteins; D011828:Radiation Chimera; D017455:Receptors, IgE / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D060149:Tetraspanin 30; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism; D054462:p21-Activated Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000199:Actins; D015703:Antigens, CD; D001704:Biopolymers; C554587:Cd63 protein, mouse; D008562:Membrane Glycoproteins; D010980:Platelet Membrane Glycoproteins; D017455:Receptors, IgE; D011993:Recombinant Fusion Proteins; D060149:Tetraspanin 30; D007073:Immunoglobulin E; D000001:Calcimycin; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; D001619:beta-N-Acetylhexosaminidases