A Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells

dc.contributor.authorStaser, Karl
dc.contributor.authorShew, Matthew A.
dc.contributor.authorMichels, Elizabeth G.
dc.contributor.authorMwanthi, Muithi M.
dc.contributor.authorYang, Feng-Chun
dc.contributor.authorClapp, D. Wade
dc.contributor.authorPark, Su-Jung
dc.contributor.departmentPediatrics, School of Medicine
dc.date.accessioned2025-06-12T13:43:35Z
dc.date.available2025-06-12T13:43:35Z
dc.date.issued2013
dc.description.abstractMast cells coordinate allergy and allergic asthma and are crucial cellular targets in therapeutic approaches to inflammatory disease. Allergens cross-link immunoglobulin E bound at high-affinity receptors on the mast cell's surface, causing release of preformed cytoplasmic granules containing inflammatory molecules, including histamine, a principal effector of fatal septic shock. Both p21 activated kinase 1 (Pak1) and protein phosphatase 2A (PP2A) modulate mast cell degranulation, but the molecular mechanisms underpinning these observations and their potential interactions in common or disparate pathways are unknown. In this study, we use genetic and other approaches to show that Pak1's kinase-dependent interaction with PP2A potentiates PP2A's subunit assembly and activation. PP2A then dephosphorylates threonine 567 of Ezrin/Radixin/Moesin (ERM) molecules that have been shown to couple F-actin to the plasma membrane in other cell systems. In our study, the activity of this Pak1-PP2A-ERM axis correlates with impaired systemic histamine release in Pak1(-/-) mice and defective F-actin rearrangement and impaired degranulation in Ezrin disrupted (Mx1Cre(+)Ezrin(flox/flox)) primary mast cells. This heretofore unknown mechanism of mast cell degranulation provides novel therapeutic targets in allergy and asthma and may inform studies of kinase regulation of cytoskeletal dynamics in other cell lineages.
dc.eprint.versionAuthor's manuscript
dc.identifier.citationStaser K, Shew MA, Michels EG, et al. A Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells. Exp Hematol. 2013;41(1):56-66.e2. doi:10.1016/j.exphem.2012.10.001
dc.identifier.urihttps://hdl.handle.net/1805/48649
dc.language.isoen_US
dc.publisherElsevier
dc.relation.isversionof10.1016/j.exphem.2012.10.001
dc.relation.journalExperimental Hematology
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectActins
dc.subjectCytoskeletal proteins
dc.subjectMembrane proteins
dc.subjectSignal transduction
dc.titleA Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells
dc.typeArticle
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