P21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics

Jayme D. Allen, Zahara M. Jaffer, Su Jung Park, Sarah Burgin, Clemens Hofmann, Mary Ann Sells, Shi Chen, Ethel Derr-Yellin, Elizabeth G. Michels, Andrew McDaniel, Waylan K. Bessler, David A. Ingram, Simon J. Atkinson, Jeffrey B. Travers, Jonathan Chernoff, D. Wade Clapp

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

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, 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 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.

Original languageEnglish (US)
Pages (from-to)2695-2705
Number of pages11
JournalBlood
Volume113
Issue number12
DOIs
StatePublished - Mar 19 2009

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Allen, J. D., Jaffer, Z. M., Park, S. J., Burgin, S., Hofmann, C., Sells, M. A., Chen, S., Derr-Yellin, E., Michels, E. G., McDaniel, A., Bessler, W. K., Ingram, D. A., Atkinson, S. J., Travers, J. B., Chernoff, J., & Clapp, D. W. (2009). P21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics. Blood, 113(12), 2695-2705. https://doi.org/10.1182/blood-2008-06-160861