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.
Highlights
The protein kinase p21-activated kinase-1 (Pak1) stimulates mast cell degranulation, but the role of the more abundant isoform Pak2 in these cells is unknown
We previously reported that Pak1 loss in mouse bone marrow-derived mast cells (BMMCs) was associated with reduced MAPK phosphorylation (Erk1/2 and p38), resulting in impaired stem cell factor-mediated migration in vitro and in vivo [11]
Genetic Disruption of Murine Pak2—Previously, we reported that Pak1 was a positive regulator of antigen-mediated degranulation in BMMCs via regulation of extracellular calcium flux [10]
Summary
The protein kinase Pak stimulates mast cell degranulation, but the role of the more abundant isoform Pak in these cells is unknown. 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, Pak, is expressed at very high levels in mast cells, but its function is unknown. We show that Pak loss in murine bone marrow-derived mast cells, unlike loss of Pak, 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 p38MAPK, and is reversed upon treatment with a Rho-specific inhibitor.
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