title: Pak2 kinase restrains mast cell FcεRI receptor signaling through modulation of Rho protein guanine nucleotide exchange factor (GEF) activity.
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.
authors.affiliation: Cancer Biology Program, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Kosoff
authors.forename: Hoi Yee
authors.initials: HY
authors.lastname: Chow
authors.forename: Maria
authors.initials: M
authors.lastname: Radu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
mesh_terms: D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D017931:DNA Primers; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D017455:Receptors, IgE / Q000378:metabolism*; D015398:Signal Transduction; D054462:p21-Activated Kinases
chemical_list: D017931:DNA Primers; D020662:Guanine Nucleotide Exchange Factors; D017455:Receptors, IgE; C515909:Pak2 protein, mouse; D054462:p21-Activated Kinases; D002118:Calcium