scholarly journals Co-Stimulation of Purinergic P2X4 and Prostanoid EP3 Receptors Triggers Synergistic Degranulation in Murine Mast Cells

2019 ◽  
Vol 20 (20) ◽  
pp. 5157 ◽  
Author(s):  
Yoshida ◽  
Tajima ◽  
Nagano ◽  
Obayashi ◽  
Ito ◽  
...  
Keyword(s):  
Mast Cells ◽  
Kinase Inhibitors ◽  
Type I ◽  
Cooperative Effects ◽  
Ige Receptors ◽  
Mouse Ear ◽  
The Common ◽  
G Protein Coupled ◽  
Mouse Ear Edema

Mast cells (MCs) recognize antigens (Ag) via IgE-bound high affinity IgE receptors (FcεRI) and trigger type I allergic reactions. FcεRI-mediated MC activation is regulated by various G protein-coupled receptor (GPCR) agonists. We recently reported that ionotropic P2X4 receptor (P2X4R) stimulation enhanced FcεRI-mediated degranulation. Since MCs are involved in Ag-independent hypersensitivity, we investigated whether co-stimulation with ATP and GPCR agonists in the absence of Ag affects MC degranulation. Prostaglandin E2 (PGE2) induced synergistic degranulation when bone marrow-derived MCs (BMMCs) were co-stimulated with ATP, while pharmacological analyses revealed that the effects of PGE2 and ATP were mediated by EP3 and P2X4R, respectively. Consistently, this response was absent in BMMCs prepared from P2X4R-deficient mice. The effects of ATP and PGE2 were reduced by PI3 kinase inhibitors but were insensitive to tyrosine kinase inhibitors which suppressed the enhanced degranulation induced by Ag and ATP. MC-dependent PGE2-triggered vascular hyperpermeability was abrogated in a P2X4R-deficient mouse ear edema model. Collectively, our results suggest that P2X4R signaling enhances EP3R-mediated MC activation via a different mechanism to that involved in enhancing Ag-induced responses. Moreover, the cooperative effects of the common inflammatory mediators ATP and PGE2 on MCs may be involved in Ag-independent hypersensitivity in vivo.

Imidazolidinyl urea activates mast cells via MRGPRX2 to induce non-histaminergic allergy

2021 ◽  
Author(s):  
Jiapan Gao ◽  
Delu Che ◽  
Xueshan Du ◽  
Yi Zheng ◽  
Huiling Jing ◽  
...  
Keyword(s):  
Contact Dermatitis ◽  
Mast Cells ◽  
Pharmaceutical Products ◽  
Drug Induced ◽  
Inflammatory Infiltration ◽  
Local Inflammatory Response ◽  
Allergic Contact ◽  
G Protein Coupled

Abstract Imidazolidinyl urea (IU) is used as an antimicrobial preservative in cosmetic and pharmaceutical products. IU induces allergic contact dermatitis, however, the mechanism has not yet been elucidated. Mas-related G protein-coupled receptor-X2 (MRGPRX2) triggers drug-induced pseudo-allergic reactions. The aims of this study were to determine whether IU activated mast cells through MRGPRX2 to further trigger contact dermatitis. Wild-type (WT) and KitW-sh/HNihrJaeBsmJNju (MUT) mice were treated with IU to observe its effects on local inflammation and mast cells degranulation in vivo. Laboratory of allergic disease 2 cells were used to detect calcium mobilization and release of inflammatory mediators in vitro. WT mice showed a severe local inflammatory response and contact dermatitis, whereas only slight inflammatory infiltration was observed in MUT mice. Thus, MRGPRX2 mediated the IU-induced activation of mast cells. However, histamine, a typical allergen, was not involved in this process. Tryptase expressed by mast cells was the major non-histaminergic inflammatory mediator of contact dermatitis. IU induced anaphylactic reaction via MRGPRX2 and further triggering non-histaminergic contact dermatitis, which explained why antihistamines are clinically ineffective against some chronic dermatitis.

Role of common cytokine receptor γ chain (γc)– and Jak3-dependent signaling in the proliferation and survival of murine mast cells

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2172-2180 ◽  
Author(s):  
Kotaro Suzuki ◽  
Hiroshi Nakajima ◽  
Norihiko Watanabe ◽  
Shin-ichiro Kagami ◽  
Akira Suto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cells ◽  
Cytokine Receptor ◽  
Type I ◽  
Dependent Manner ◽  
Type Ii ◽  
Wild Type ◽  
Peritoneal Mast Cells ◽  
The Common

Abstract The regulatory roles of the common cytokine receptor γ chain (γc)– and Jak3-dependent signaling in the proliferation and survival of mast cells were determined using γc-deficient (γc−) and Jak3-deficient (Jak3−) mice. Although the mast cells in γc− and Jak3− mice were morphologically indistinguishable from those in wild-type mice, the number of peritoneal mast cells was decreased in γc− and Jak3− mice as compared with that in wild-type mice. Among γc-related cytokines, interleukin (IL)-4 and IL-9, but not IL-2, IL-7, or IL-15, enhanced the proliferation and survival of bone marrow–derived mast cells (BMMCs) from wild-type mice. However, the effects of IL-4 and IL-9 were absent in BMMCs from γc− and Jak3−mice. In addition, IL-4Rα, γc, and Jak3, but not IL-2Rβ or IL-7Rα, were expressed in BMMCs. In contrast, IL-13 did not significantly induce the proliferation and survival of BMMCs even from wild-type mice, and IL-13Rα1 was not expressed in BMMCs. Furthermore, IL-4 phosphorylated the 65-kd isoform of Stat6 in BMMCs from wild-type mice but not from γc− and Jak3− mice. These results indicate that γc- and Jak3-dependent signaling is essential for IL-4– and IL-9–induced proliferation and survival of murine mast cells, that the effects of IL-4 are mediated by type I IL-4R and that type II IL-4R is absent on mast cells, and that IL-4 phosphorylates the 65-kd isoform of Stat6 in mast cells in a γc- and Jak3-dependent manner.

scholarly journals Regulation of type I adenylyl cyclase by calmodulin kinase IV in vivo.

1996 ◽  
Vol 16 (11) ◽  
pp. 6075-6082 ◽  
Author(s):  
G A Wayman ◽  
J Wei ◽  
S Wong ◽  
D R Storm
Keyword(s):  
Adenylyl Cyclase ◽  
Long Term Potentiation ◽  
Type I ◽  
Cam Kinase ◽  
Regulatory Systems ◽  
Calmodulin Kinase ◽  
Term Potentiation ◽  
G Protein Coupled ◽  
Cam Kinase Iv

Type I adenylyl cyclase is a neurospecific enzyme that is stimulated by Ca2+ and calmodulin (CaM). This enzyme couples the Ca2+ and cyclic AMP (cAMP) regulatory systems in neurons, and it may play an important role for some forms of synaptic plasticity. Mutant mice lacking type I adenylyl cyclase show deficiencies in spatial memory and altered long-term potentiation (Z. Wu, S. A. Thomas, Z. Xia, E. C. Villacres, R. D. Palmiter, and D. R. Storm, Proc. Natl. Acad. Sci. USA 92:220-224, 1995). Although type I adenylyl cyclase is synergistically stimulated by Ca2+ and G-protein-coupled receptors in vivo, very little is known about mechanisms for inhibition of the enzyme. Here, we report that type I adenylyl cyclase is inhibited by CaM kinase IV in vivo. Expression of constitutively active or wild-type CaM kinase IV inhibited Ca2+ stimulation of adenylyl cyclase activity without affecting basal or forskolin-stimulated activity. Type I adenylyl cyclase has two CaM kinase IV consensus phosphorylation sequences near its CaM binding domain at Ser-545 and Ser-552. Conversion of either serine to alanine by mutagenesis abolished CaM kinase IV inhibition of adenylyl cyclase. This suggests that the activity of this enzyme may be directly inhibited by CaM kinase IV phosphorylation. Type VIII adenylyl cyclase, another enzyme stimulated by CaM, was not inhibited by CaM kinase II or IV. We propose that CaM kinase IV may function as a negative feedback regulator of type I adenylyl cyclase and that CaM kinases may regulate cAMP levels in some cells.

scholarly journals Regulation of anaphylactic responses by phosphatidylinositol phosphate kinase type I α

2005 ◽  
Vol 201 (6) ◽  
pp. 859-870 ◽  
Author(s):  
Junko Sasaki ◽  
Takehiko Sasaki ◽  
Masakazu Yamazaki ◽  
Kunie Matsuoka ◽  
Choji Taya ◽  
...  
Keyword(s):  
Mast Cells ◽  
Actin Polymerization ◽  
Negative Regulator ◽  
Type I ◽  
Filamentous Actin ◽  
Critical Signal ◽  
Cell Functions ◽  
Phosphatidylinositol Phosphate

The membrane phospholipid phosphatidylinositol 4, 5-bisphosphate [PI(4,5)P2] is a critical signal transducer in eukaryotic cells. However, the physiological roles of the type I phosphatidylinositol phosphate kinases (PIPKIs) that synthesize PI(4,5)P2 are largely unknown. Here, we show that the α isozyme of PIPKI (PIPKIα) negatively regulates mast cell functions and anaphylactic responses. In vitro, PIPKIα-deficient mast cells exhibited increased degranulation and cytokine production after Fcε receptor-I cross-linking. In vivo, PIPKIα−/− mice displayed enhanced passive cutaneous and systemic anaphylaxis. Filamentous actin was diminished in PIPKIα−/− mast cells, and enhanced degranulation observed in the absence of PIPKIα was also seen in wild-type mast cells treated with latrunculin, a pharmacological inhibitor of actin polymerization. Moreover, the association of FcεRI with lipid rafts and FcεRI-mediated activation of signaling proteins was augmented in PIPKIα−/− mast cells. Thus, PIPKIα is a negative regulator of FcεRI-mediated cellular responses and anaphylaxis, which functions by controlling the actin cytoskeleton and dynamics of FcεRI signaling. Our results indicate that the different PIPKI isoforms might be functionally specialized.

Morin inhibits Fyn kinase in mast cells and IgE-mediated type I hypersensitivity response in vivo

2009 ◽  
Vol 77 (9) ◽  
pp. 1506-1512 ◽  
Author(s):  
Jie Wan Kim ◽  
Jun Ho Lee ◽  
Bang Yeon Hwang ◽  
Se Hwan Mun ◽  
Na Young Ko ◽  
...  
Keyword(s):  
Mast Cells ◽  
Type I ◽  
Hypersensitivity Response ◽  
Fyn Kinase ◽  
Ige Mediated ◽  
Type I Hypersensitivity

scholarly journals Hyperactivation of P21ras and the Hematopoietic-Specific Rho Gtpase, Rac2, Cooperate to Alter the Proliferation of Neurofibromin-Deficient Mast Cells in Vivo and in Vitro

2001 ◽  
Vol 194 (1) ◽  
pp. 57-70 ◽  
Author(s):  
David A. Ingram ◽  
Kelly Hiatt ◽  
Alastair J. King ◽  
Lucy Fisher ◽  
Rama Shivakumar ◽  
...  
Keyword(s):  
Mast Cells ◽  
Cross Talk ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Cell Lineage ◽  
Neurofibromatosis Type ◽  
Type I ◽  
Erk Pathway

Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type I (NF1), a disease characterized by the formation of cutaneous neurofibromas infiltrated with a high density of degranulating mast cells. A hallmark of cell lines generated from NF1 patients or Nf1-deficient mice is their propensity to hyperproliferate. Neurofibromin, the protein encoded by NF1, negatively regulates p21ras activity by accelerating the conversion of Ras-GTP to Ras-GDP. However, identification of alterations in specific p21ras effector pathways that control proliferation in NF1-deficient cells is incomplete and critical for understanding disease pathogenesis. Recent studies have suggested that the proliferative effects of p21ras may depend on signaling outputs from the small Rho GTPases, Rac and Rho, but the physiologic importance of these interactions in an animal disease model has not been established. Using a genetic intercross between Nf1+/− and Rac2−/− mice, we now provide genetic evidence to support a biochemical model where hyperactivation of the extracellular signal–regulated kinase (ERK) via the hematopoietic-specific Rho GTPase, Rac2, directly contributes to the hyperproliferation of Nf1-deficient mast cells in vitro and in vivo. Further, we demonstrate that Rac2 functions as mediator of cross-talk between phosphoinositide 3-kinase (PI-3K) and the classical p21ras-Raf-Mek-ERK pathway to confer a distinct proliferative advantage to Nf1+/− mast cells. Thus, these studies identify Rac2 as a novel mediator of cross-talk between PI-3K and the p21ras-ERK pathway which functions to alter the cellular phenotype of a cell lineage involved in the pathologic complications of a common genetic disease.

scholarly journals Inhibition of PRMT1 Mediated FLT3 Arginine Methylation As a Potent Therapeutic Strategy for MLL-r ALL

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 892-892
Author(s):  
Yinghui Zhu ◽  
Xin He ◽  
Haojie Dong ◽  
Jie Sun ◽  
Hanying Wang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Combination Treatment ◽  
Kinase Inhibitors ◽  
Arginine Methylation ◽  
Mass Spectrometry Analysis ◽  
Type I ◽  
Mrna Levels ◽  
Spectrometry Analysis ◽  
Dismal Prognosis

Abstract Mixed-lineage leukemia-rearranged (MLL-r) ALL, seen in 70% of infant ALL, has a dismal prognosis compared to those with wild type MLL1 gene. Transcriptional profiling has identified Fms-like receptor tyrosine kinase 3 (FLT3) as one of the most significantly upregulated genes in MLL-r ALL. The highly expressed FLT3 protein is activated by the autocrine ligand, making the kinase a therapeutic target. FLT3 tyrosine kinase inhibitors (TKIs) such as PKC412, although effective in kinase inhibition, partially impair survival of MLL-r ALL cells and clinical trial results are not promising, promoting us to ask whether FLT3 regulates the ALL cells survival also through a kinase-independent mechanism. Herein, we report the finding of dimethylated arginines on FLT3, detected through mass spectrometry analysis of a MLL-r ALL specimen and a MLL-r ALL line SEM. The most conserved and enriched of dimethylated arginines are residues R972/R973. Using home-made arginine methylation (R-Me) antibody, we found that PRMT1, which is responsible for most type I arginine methyltransferases activity, catalyzes FLT3 methylation. Immunoblot (IB) analysis validated the expression of FLT3 R-Me in MLL-r ALL samples (6 out of 6) and MLL-r ALL lines (4 out of 4). Analysis of the GEO dataset (GSE13204) revealed that PRMT1 mRNA levels are increased in MLL-r ALL relative to normal cells (MLL-r, n=70 vs. normal, n=73, p<0.0001). We studied FLT3 R-Me biological function using two approaches that specifically blocked FLT3 methylation levels: cells expressing FLT3 methylation deficient construct (R972/973K, arginine [R] to lysine [K]) exhibited reduced survival (BaF3: FLT3-WT 98.5±0.11% vs. R972/973K 71.5±0.53%, p=0.0004); knockdown of PRMT1 in SEM cells also had an inhibitory effect (siCtrl 95.1±0.1% vs. siPRMT1 74.7±0.5%, p=0.0007). Moreover, the type I arginine methyltransferase inhibitor MS023 (5 µM) treatment markedly induced apoptosis of primary ALL cells but spared normal counterparts from healthy donors (ALL: vehicle 10.4±0.4% vs. MS023 23.7±0.8%, n=4; p<0.0001; normal CD19+: 8.3±0.3% vs. 8.2±0.1%, n=3, p=0.86). Interestingly, inhibition of FLT3 methylation decreased FLT3 phosphorylation at tyrosine 969 (Y969) but not Y589/591 or Y842. Expression of R972/973K decreased FLT3 downstream signaling like phospho-STAT5 and -AKT to a greater extent than that of Y969F mutant (Y to phenylalanine [F] substitution, mimics loss of Y phosphorylation). Next, FLT3 WT, R972/973K or Y969F transduced primary MLL-r ALL cells were transplanted into NSGS mice for analysis of leukemia development (n=6/group). Mice transplanted with FLT3 Y969F MLL-r ALL had longer survival relative to FLT-WT injected animals (p=0.0031), and the median survival was further extended in mice injected with R972/973K mutant compared with FLT3 Y969F MLL-r ALL (p=0.0007). Additionally, PKC412 treatment alone did not alter FLT3 R-Me, and high FLT3 methylation level in SEM cells was not affected by FLT3 ligand stimulation, confirming that the function of R-Me is independent of FLT3 phosphorylation. Importantly, we observed that the combination of MS023 with PKC412 significantly induced a higher rate of apoptosis in primary MLL-r ALL cells compared with each drug alone (control, 10±0.43%, MS023, 21.1±1.2%, PKC412, 21.5±0.11%, combination, 39.8±2.9%, PKC412 vs combination, p<0.01, n=4). We further tested the effects of in vivo administration of MS023 plus PKC412 on primary MLL-r ALL cells xenografted in NSGS mice. Following engraftment >1% in peripheral blood, mice were subdivided into four groups and treated with vehicle, PKC412 (100 mg/kg, i.g.), MS023 (80 mg/kg, i.p, bid), or the combination (n=7/group) for 4 weeks. The BM tumor burden of CD45+ CD19+ cells was reduced in single drug-treated mice cohorts, with further reduction after combination treatment (vehicle, 94.4±0.5%, PKC412, 50.2±6.3%, MS023, 55.6±4.5%, combination, 30.7±4.9%, PKC412 vs. combination, p<0.001). Secondary transplantation of BM cells from mice receiving combination treatment resulted in significantly reduced BM engraftment at 16 weeks compared to PKC412 treatment alone (PKC412, 62.2±4.9%, combination, 8.4±5.1%, n=5, p<0.0001), indicating reduced leukemia initiating capacity. Our results support further exploring the molecular function of FLT3 R-Me. We will determine whether PRMT1 and FLT3 methylation are potential druggable targets in MLL-r ALL. Disclosures Konopleva: Stemline Therapeutics: Research Funding.

scholarly journals The Response of Tissue Mast Cells to TLR3 Ligand Poly(I:C) Treatment

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Piotr Witczak ◽  
Ewa Brzezińska-Błaszczyk ◽  
Justyna Agier
Keyword(s):  
Mast Cells ◽  
Bacterial Infections ◽  
Lymphatic Vessels ◽  
Poly I:C ◽  
Type I ◽  
Viral Dsrna ◽  
Mhc I ◽  
Antiviral Immune Response ◽  
Cellular Antiviral Response

Mast cells (MCs) are found mainly at the anatomical sites exposed to the external environment; thus, they are localized close to blood vessels, lymphatic vessels, and a multitude of immune cells. Moreover, those cells can recognize invading pathogens through a range of surface molecules known as pathogen recognition receptors (PRRs), mainly Toll-like receptors (TLRs). MCs are extensively engaged in the control and clearance of bacterial infections, but much less is known about their contribution to antiviral host response as well as pathomechanisms of virus-induced diseases. In the study, we employed in vivo differentiated mature tissue mast cells freshly isolated from rat peritoneal cavity. Here, we demonstrated that rat peritoneal mast cells (rPMCs) express viral dsRNA-specific TLR3 molecule (intracellularly and on the cell surface) as well as other proteins associated with cellular antiviral response: IRF3, type I and II IFN receptors, and MHC I. We found that exposure of rPMCs to viral dsRNA mimic, i.e., poly(I:C), induced transient upregulation of surface TLR3 (while temporarily decreased TLR3 intracellular expression), type II IFN receptor, and MHC I. TLR3 ligand-stimulated rPMCs did not degranulate but generated and/or released type I IFNs (IFN-α and IFNβ) as well as proinflammatory lipid mediators (cysLTs), cytokines (TNF, IL-1β), and chemokines (CCL3, CXCL8). We documented that rPMC priming with poly(I:C) did not affect FcεRI-dependent degranulation. However, their costimulation with TLR3 agonist and anti-IgE led to a significant increase in cysLT and TNF secretion. Our findings confirm that MCs may serve as active participants in the antiviral immune response. Presented data on modulated FcεRI-mediated MC secretion of mediators upon poly(I:C) treatment suggests that dsRNA-type virus infection could influence the severity of allergic reactions.

scholarly journals The Superimposed Deubiquitination Effect of OTULIN and Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) Nsp11 Promotes Multiplication of PRRSV

2018 ◽  
Vol 92 (9) ◽  
Author(s):  
Yanxin Su ◽  
Peidian Shi ◽  
Lilin Zhang ◽  
Dong Lu ◽  
Chengxue Zhao ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Cell Model ◽  
Nuclear Factor Κb ◽  
Cellular Protein ◽  
Type I Interferons ◽  
Respiratory Syndrome Virus ◽  
Type I ◽  
Cooperative Effects ◽  
Superimposed Effect

ABSTRACTLinear ubiquitination plays an important role in the regulation of the immune response by regulating nuclear factor κB (NF-κB). The linear ubiquitination-specific deubiquitinase ovarian tumor domain deubiquitinase with linear linkage specificity (OTULIN) can control the immune signaling transduction pathway by restricting the Met1-linked ubiquitination process. In our study, the porcine OTLLIN gene was cloned and deubiquitin functions were detected in a porcine reproductive and respiratory syndrome virus (PRRSV)-infected-cell model. PRRSV infection promotes the expression of the OTULIN gene; in turn, overexpression of OTULIN contributes to PRRSV proliferation. There is negative regulation of innate immunity with OTULIN during viral infection. The cooperative effects of swine OTULIN and PRRSV Nsp11 potentiate the ability to reduce levels of cellular protein ubiquitin associated with innate immunity. Importantly, PRRSV Nsp11 recruits OTULIN through a nonenzymatic combination to enhance its ability to remove linear ubiquitination targeting NEMO, resulting in a superimposed effect that inhibits the production of type I interferons (IFNs). Our report presents a new model of virus utilization of the ubiquitin-protease systemin vivofrom the perspective of the viral proteins that interact with cell deubiquitination enzymes, providing new ideas for prevention and control of PRRSV.IMPORTANCEDeubiquitination effects of swine OTULIN were identified. The interaction between porcine OTULIN and PRRSV Nsp11 is dependent on the OTU domain. PRRSV Nsp11 recruits OTULIN through a nonenzymatic combination to promote removal of linear ubiquitination targeting NEMO, resulting in a superimposed effect that inhibits the production of type I IFNs.

p21-Activated Kinase 1 Regulates Hyperproliferation of Nf1 Haploinsufficient Mast Cells In Vitro and In Vivo Via Activation of the MAPK Pathway.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3063-3063
Author(s):  
Andrew S. McDaniel
Keyword(s):  
Mast Cells ◽  
Mammalian Cells ◽  
Rho Gtpase ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Type I ◽  
Wild Type ◽  
Kit Ligand

Abstract p21-activated kinases (Paks) are downstream mediators of Rho GTPase proteins and have been implicated in yeast and immortalized cells as positive regulators of MAPK pathway members in modulating cell growth and cytoskeletal functions. However, their role in primary mammalian cells has not been described. NF1 encodes neurofibromin, which negatively regulates p21Ras activity by stimulating its intrinsic GTPase activity, and accelerating hydrolysis of Ras from the GTP to the GDP confirmation. Disruption of the NF1 locus results in neurofibromatosis type I (NF1), an inherited disorder characterized by the development of neurofibromas that contain large numbers of degranulating mast cells that have been implicated in tumor progression. Utilizing a genetic intercross of Pak 1−/− mice with mice haploinsufficient at the Nf1 locus, we studied the role of Pak1 in the context of normal and hyperactivated Ras-MAPK signaling in primary inflammatory mast cells. Pak1 was found to directly contribute to Ras-dependent signaling by modulating both Raf-1, Mek-1 and ERK1/2 activation. Loss of Pak1 fully corrects the hyperphosphorylation of ERK1/2 found in Nf1+/− mast cells to that of wild type controls. Deletion of Pak1 in Nf1+/− mast cells is associated with a correction of Kit ligand mediated proliferation to wild type levels in vitro. Further, after subcutaneous administration of Kit ligand via micro osmotic pumps, which is an established model that stimulates local proliferation of mast cells in vivo (Ingram, JEM 2001), we confirmed that genetic disruption of Pak1 corrects the proliferation of Nf1+/− mast cells in vivo to that of wild type controls. These data provide direct genetic evidence that Pak1 modulates the Ras-Raf-Mek-Erk pathway and identifies a specific molecular target within the inflammatory tumor microenvironment for the treatment or prevention of neurofibromas.

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