Pak2 Kinase Restrains Mast Cell FcϵRI Receptor Signaling through Modulation of Rho Protein Guanine Nucleotide Exchange Factor (GEF) Activity

Kosoff, Rachelle; Chow, Hoi Yee; Radu, Maria; Chernoff, Jonathan

doi:10.1074/jbc.m112.422295

Cited by 29 publications

(31 citation statements)

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“…In contrast to these findings, previous studies showed that deletion of either Pak1 or Pak3 is tolerated, and mice lacking either of these genes do not display significant vascular defects (12). These results are consistent with the fact that Pak2 is the main isoform expressed in ECs (35) and the idea that Pak1 and Pak2 have distinct and often opposing roles in mediating various cellular events, as has been suggested by a number of recent studies (36)(37)(38).…”

Section: Discussioncontrasting

confidence: 55%

p21-Activated Kinase 2 Regulates Endothelial Development and Function through the Bmk1/Erk5 Pathway

Radu

Lyle²,

Hoeflich³

et al. 2015

Molecular and Cellular Biology

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c p21-activated kinases (Paks) have been shown to regulate cytoskeleton rearrangements, cell proliferation, attachment, and migration in a variety of cellular contexts, including endothelial cells. However, the role of endothelial Pak in embryo development has not been reported, and currently, there is no consensus on the endothelial function of individual Pak isoforms, in particular p21-activated kinase 2 (Pak2), the main Pak isoform expressed in endothelial cells. In this work, we employ genetic and molecular studies that show that Pak2, but not Pak1, is a critical mediator of development and maintenance of endothelial cell function. Endothelial depletion of Pak2 leads to early embryo lethality due to flawed blood vessel formation in the embryo body and yolk sac. In adult endothelial cells, Pak2 depletion leads to severe apoptosis and acute angiogenesis defects, and in adult mice, endothelial Pak2 deletion leads to increased vascular permeability. Furthermore, ubiquitous Pak2 deletion is lethal in adult mice. We show that many of these defects are mediated through a newly unveiled Pak2/Bmk1 pathway. Our results demonstrate that endothelial Pak2 is essential during embryogenesis and also for adult blood vessel maintenance, and they also pinpoint the Bmk1/ Erk5 pathway as a critical mediator of endothelial Pak2 signaling.T he p21-activated kinases (Paks) are evolutionarily conserved serine/threonine kinases that act downstream of the Rho family GTPases, Rac1 and Cdc42, to regulate numerous cellular processes. p21-activated kinase 1 (Pak1) to Pak3, the group I Paks, are expressed in numerous tissues with Pak1 being predominantly expressed in brain, muscle, gastrointestinal tract, and thyroid and Pak3 being predominantly expressed in brain (1, 2). Compared to the more restricted expression of Pak1 and Pak3, Pak2 is ubiquitously expressed (3-9). Group I Pak family members share a high degree of homology (3), but they may play distinct roles as observed by the significantly different phenotypes of knockout (KO) animal models. While Pak1 KO and Pak3 KO mice are viable (10, 11), Pak2 KO mice are embryonic lethal at embryonic day 8.5 (E8.5) due to multiple developmental abnormalities, including cardiovascular defects (12).The role of Pak in endothelial cell (EC) signaling has been studied in animal models (5, 13) and cultured cells (6,10,14,15). Pak signaling is critical in regulating EC attachment, migration, and lumen formation (4-9). Furthermore, Paks have been implicated in maintaining the integrity of the endothelial barrier, but conflicting data implicate various Pak isoforms as both positive and negative regulators of maintaining barrier function (5, 13, 14, 16).A few in vivo studies have specifically implicated Pak2 in vascular pathways. A study in Danio rerio showed that pak2a, one of two Pak2 orthologs in this organism, plays an important role in cerebral vascular maintenance (5). In this study, chemical mutagenesis of the pak2a gene and pak2a-targeting morpholinos caused cerebral hemorrhage, implicating this...

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Section: Discussioncontrasting

confidence: 55%

p21-Activated Kinase 2 Regulates Endothelial Development and Function through the Bmk1/Erk5 Pathway

Radu

Lyle²,

Hoeflich³

et al. 2015

Molecular and Cellular Biology

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“…In this regard, p21-activated kinases (Pak) have been recently characterized to transduce the Fyn-dependent signaling to the cytoskeleton. Pak1 is necessary for F-actin arrangement [25], while Pak2 deficiency increases RhoA-GTPase signaling activity to downstream effectors, including myosin light chain and MAPK activity, resulting in degranulation and cytokine exocytosis [26]. Figure 1B summarizes the content of this section and shows the newly identified proteins involved in the Fyn-dependent signaling.…”

Section: Fynmentioning

confidence: 99%

“…Shin et al described a previously unknown mechanism of mammalian target of rapamycin (mTOR) regulation also in mast cell biology [24][25][26]. mTOR is an evolutionarily conserved serine/threonine kinase activated by PI3K/Akt signaling.…”

Section: Fynmentioning

confidence: 99%

Mast cell activation: A complex interplay of positive and negative signaling pathways

Sibilano¹,

2014

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Mast cells regulate the immunological responses causing allergy and autoimmunity, and contribute to the tumor microenvironment through generation and secretion of a broad array of preformed, granule-stored and de novo synthesized bioactive compounds. The release and production of mast cell mediators is the result of a coordinated signaling machinery, followed by the FcεRI and FcγR antigen ligation. In this review, we present the latest understanding of FcεRI and FcγR signaling, required for the canonical mast cell activation during allergic responses and anaphylaxis. We then describe the cooperation between the signaling of FcR and other recently characterized membrane-bound receptors (i.e., IL-33R and thymic stromal lymphopoietin receptor) and their role in the chronic settings, where mast cell activation is crucial for the development and the sustainment of chronic diseases, such as asthma or airway inflammation. Finally, we report how the FcR activation could be used as a therapeutic approach to treat allergic and atopic diseases by mast cell inactivation. Understanding the magnitude and the complexity of mast cell signaling is necessary to identify the mechanisms underlying the potential effector and regulatory roles of mast cells in the biology and pathology of those disease settings in which mast cells are activated.Keywords: FcεRI r FcγR r IL-33 r mast cells r TSLP IntroductionMast cells originate in the BM from a lineage-specific multipotent hematopoietic progenitor, circulate as CD34 + precursors until they migrate to tissues and mature into effector cells in the proximity of organs and blood vessels. Mast cells respond to antigenic stimulation through the cross-linking of immunoglobulin E (IgE) bound to high-affinity receptors for IgE (FcεRI) and the activation of the FcγR after IgG binding (reviewed in [1,2]). Upon activation, mast cells release either preformed, granule-stored mediators, such as histamine and proteases, or newly generated mediators, such as eicosanoids, cytokines, and chemokines [3]. Although the basic molecular mechanisms of Ig:Fc activation have been extensively studied in the past 15 years [4][5][6], new molecules regulating the Correspondence: Dr. Barbara Frossi e-mail: barbara.frossi@uniud.it FcR-signaling cascades have recently been characterized, suggesting not only a still vivid interest in the field of mast cell activation and signaling, but also in identifying putative new therapeutic targets for intervention in mast cell dependent disorders. This review will focus on three aspects of mast cell activation/function. First, we give an essential but complete overview of the FcR-mediated activation in mast cells and report on recent advances in IgE-and IgG-mediated signaling. For clarity, we will dissect and analyze the signals derived from each pathway, with particular attention to the newly identified positive or negative molecular players describing -when possible -their implication toward degranulation and cytokine production. Second, we highlight the growing interest aroun...

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“…WB technique on day 5 megakaryocytes was carried out as previously described by our laboratory. 13 Recombinant mouse TPO was from Shenandoah Biotechnology. Interleukin 3 (IL-3) and IL-6 were purchased from PeproTech.…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

“…10 After their activation by the r GTPases, Rac1 and Cdc42, Paks phosphorylate dozens of effector proteins to regulate the mitogenactivated protein kinase signaling and cytoskeletal remodeling. [11][12][13][14] Accordingly, the Paks regulate numerous hematopoietic processes, including hematopoietic stem cell engraftment and homing to the bone marrow, assembly of the actin cytoskeleton, and chemotaxis. 15 In addition, Paks promote hematopoiesis by regulating Raf-1 and Mek-1 activation to drive Erk1/2 activation, resulting in proper hematopoietic function.…”

Section: Introductionmentioning

confidence: 99%

Pak2 restrains endomitosis during megakaryopoiesis and alters cytoskeleton organization

Kosoff

Aslan

Kostyak

et al. 2015

Blood

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Pak2 Kinase Restrains Mast Cell FcϵRI Receptor Signaling through Modulation of Rho Protein Guanine Nucleotide Exchange Factor (GEF) Activity

Cited by 29 publications

References 42 publications

p21-Activated Kinase 2 Regulates Endothelial Development and Function through the Bmk1/Erk5 Pathway

p21-Activated Kinase 2 Regulates Endothelial Development and Function through the Bmk1/Erk5 Pathway

Mast cell activation: A complex interplay of positive and negative signaling pathways

Pak2 restrains endomitosis during megakaryopoiesis and alters cytoskeleton organization

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