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J Biol Chem. 2013 Jan 11;288(2):974-83. doi: 10.1074/jbc.M112.422295. Epub 2012 Nov 30.

Pak2 kinase restrains mast cell FcεRI receptor signaling through modulation of Rho protein guanine nucleotide exchange factor (GEF) activity.

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  • 1Cancer Biology Program, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Abstract

p21-activated kinase-1 (Pak1) is a serine/threonine kinase that plays a key role in mediating antigen-stimulated extracellular calcium influx and degranulation in mast cells. Another isoform in this kinase family, Pak2, is expressed at very high levels in mast cells, but its function is unknown. Here we show that Pak2 loss in murine bone marrow-derived mast cells, unlike loss of Pak1, induces increased antigen-mediated adhesion, degranulation, and cytokine secretion without changes to extracellular calcium influx. This phenotype is associated with an increase in RhoA-GTPase signaling activity to downstream effectors, including myosin light chain and p38(MAPK), and is reversed upon treatment with a Rho-specific inhibitor. Pak2, but not Pak1, negatively regulates RhoA via phosphorylation of the guanine nucleotide exchange factor GEF-H1 at an inhibitory site, leading to increased GEF-H1 microtubule binding and loss of RhoA stimulation. These data suggest that Pak2 plays a unique inhibitory role in mast cell degranulation by down-regulating RhoA via GEF-H1.

PMID:
23204526
[PubMed - indexed for MEDLINE]
PMCID:
PMC3543047
Free PMC Article
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