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

Karl Staser, Matthew A. Shew, Elizabeth G. Michels, Muithi M. Mwanthi, Feng Chun Yang, D. Clapp, Su Jung Park

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Mast 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+Ezrinflox/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.

Original languageEnglish
JournalExperimental Hematology
Volume41
Issue number1
DOIs
StatePublished - Jan 2013

Fingerprint

p21-Activated Kinases
Protein Phosphatase 2
Mast Cells
Actins
Cell Degranulation
Hypersensitivity
Phosphotransferases
Asthma
Cytoplasmic Granules
Histamine Release
Cell Lineage
Threonine
Septic Shock
Allergens
Immunoglobulin E
Histamine
Cell Membrane
ezrin
moesin
radixin

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Hematology

Cite this

A Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells. / Staser, Karl; Shew, Matthew A.; Michels, Elizabeth G.; Mwanthi, Muithi M.; Yang, Feng Chun; Clapp, D.; Park, Su Jung.

In: Experimental Hematology, Vol. 41, No. 1, 01.2013.

Research output: Contribution to journalArticle

Staser, Karl ; Shew, Matthew A. ; Michels, Elizabeth G. ; Mwanthi, Muithi M. ; Yang, Feng Chun ; Clapp, D. ; Park, Su Jung. / A Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells. In: Experimental Hematology. 2013 ; Vol. 41, No. 1.
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