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1.  Non-redundant role of CCRL2 in lung dendritic cell trafficking 
Blood  2010;116(16):2942-2949.
CCRL2 is a heptahelic transmembrane receptor that shows the highest degree of homology with CCR1, an inflammatory chemokine receptor. CCRL2 mRNA was rapidly (30 min) and transiently (2-4 hrs) regulated during dendritic cell (DC) maturation. Protein expression paralleled RNA regulation. In vivo, CCRL2 was expressed by activated DC and macrophages, but not by eosinophils and T cells. CCRL2−/− mice showed normal recruitment of circulating DC into the lung but a defective trafficking of antigen-loaded lung DC to mediastinal lymph nodes. This defect was associated to a reduction in lymph node cellularity and reduced priming of Th2 response. CCRL2−/− mice were protected in a model of OVA-induced airway inflammation with reduced leukocyte recruitment in the BAL (eosinophils and mononuclear cells) and reduced production of the Th2 cytokines IL-4 and IL-5 and chemokines CCL11 and CCL17. The central role of CCRL2 deficiency in DC was supported by the fact that adoptive transfer of CCRL2−/− antigen-loaded DC in wild type animals recapitulated the phenotype observed in knock out mice. These data show a nonredundant role of CCRL2 in lung DC trafficking and propose a role for this receptor in the control of excessive airway inflammatory responses.
doi:10.1182/blood-2009-12-259903
PMCID: PMC3389732  PMID: 20606167
2.  Phosphoinositide 3-Kinase γ Gene Knockout Impairs Postischemic Neovascularization and Endothelial Progenitor Cell Functions 
Objective
We evaluated whether phosphatidylinositol 3-kinase γ (PI3Kγ) plays a role in reparative neovascularization and endothelial progenitor cell (EPC) function.
Methods and Results
Unilateral limb ischemia was induced in mice lacking the PI3Kγ gene (PI3Kγ−/−) or expressing a catalytically inactive mutant (PI3KγKD/KD) and wild-type controls (WT). Capillarization and arteriogenesis were reduced in PI3Kγ−/− ischemic muscles resulting in delayed reperfusion compared with WT, whereas reparative neovascularization was preserved in PI3KγKD/KD. In PI3Kγ−/− muscles, endothelial cell proliferation was reduced, apoptosis was increased, and interstitial space was infiltrated with leukocytes but lacked cKit+ progenitor cells that in WT muscles typically surrounded arterioles. PI3Kγ is constitutively expressed by WT EPCs, with expression levels being upregulated by hypoxia. PI3Kγ−/− EPCs showed a defect in proliferation, survival, integration into endothelial networks, and migration toward SDF-1. The dysfunctional phenotype was associated with nuclear constraining of FOXO1, reduced Akt and eNOS phosphorylation, and decreased nitric oxide (NO) production. Pretreatment with an NO donor corrected the migratory defect of PI3Kγ−/− EPCs. PI3KγKD/KD EPCs showed reduced Akt phosphorylation, but constitutive activation of eNOS and preserved proliferation, survival, and migration.
Conclusions
We newly demonstrated that PI3Kγ modulates angiogenesis, arteriogenesis, and vasculogenesis by mechanisms independent from its kinase activity.
doi:10.1161/ATVBAHA.107.145573
PMCID: PMC2825808  PMID: 17962628
limb ischemia; angiogenesis; vasculogenesis; endothelial progenitor cells; migration
3.  Phosphoinositide 3-Kinase p110β activity: Key Role in Metabolism and Mammary Gland Cancer but not Development # 
Science signaling  2008;1(36):ra3.
The phosphoinositide 3-kinase (PI3K) pathway crucially controls metabolism and cell growth. Although different PI3K catalytic subunits are known to play distinct roles, the specific in vivo function of p110β (the product of the PIK3CB gene) is not clear. Here, we show that mouse mutants expressing a catalytically inactive PIK3CBK805R mutant survived to adulthood but showed growth retardation and developed mild insulin resistance with age. Pharmacological and genetic analyses of p110β function revealed that p110β catalytic activity is required for PI3K signaling downstream of heterotrimeric guanine nucleotide-binding (G protein)-coupled receptors as well as to sustain long term insulin signaling. In addition, PIK3CBK805R mice were protected in a model of ERBB2-driven tumor development. These findings indicate an unexpected role for p110β catalytic activity in diabetes and cancer, opening potential new avenues for therapeutic intervention.
doi:10.1126/scisignal.1161577
PMCID: PMC2694958  PMID: 18780892
4.  Protection from angiotensin II–mediated vasculotoxic and hypertensive response in mice lacking PI3Kγ 
The Journal of Experimental Medicine  2005;201(8):1217-1228.
Hypertension affects nearly 20% of the population in Western countries and strongly increases the risk for cardiovascular diseases. In the pathogenesis of hypertension, the vasoactive peptide of the renin-angiotensin system, angiotensin II and its G protein–coupled receptors (GPCRs), play a crucial role by eliciting reactive oxygen species (ROS) and mediating vessel contractility. Here we show that mice lacking the GPCR-activated phosphoinositide 3-kinase (PI3K)γ are protected from hypertension that is induced by administration of angiotensin II in vivo. PI3Kγ was found to play a role in angiotensin II–evoked smooth muscle contraction in two crucial, distinct signaling pathways. In response to angiotensin II, PI3Kγ was required for the activation of Rac and the subsequent triggering of ROS production. Conversely, PI3Kγ was necessary to activate protein kinase B/Akt, which, in turn, enhanced L-type Ca2+ channel–mediated extracellular Ca2+ entry. These data indicate that PI3Kγ is a key transducer of the intracellular signals that are evoked by angiotensin II and suggest that blocking PI3Kγ function might be exploited to improve therapeutic intervention on hypertension.
doi:10.1084/jem.20040995
PMCID: PMC2213159  PMID: 15824082
5.  Defective Rac-mediated proliferation and survival after targeted mutation of the β1 integrin cytodomain 
The Journal of Cell Biology  2002;157(3):481-492.
Cell matrix adhesion is required for cell proliferation and survival. Here we report that mutation by gene targeting of the cytoplasmic tail of β1 integrin leads to defective proliferation and survival both in vivo and in vitro. Primary murine embryonic fibroblasts (MEFs) derived from mutant homozygotes display defective cell cycle coupled to impaired activation of the FAK-PI3K-Akt and Rac-JNK signaling pathways. Expression in homozygous MEFs of a constitutively active form of Rac is able to rescue proliferation, survival, and JNK activation. Moreover, although showing normal Erk phosphorylation, mutant cells fail to display Erk nuclear translocation upon fibronectin adhesion. However, expression of the constitutively activated form of Rac restores Erk nuclear localization, suggesting that adhesion-dependent Rac activation is necessary to integrate signals directed to promote MAPK activity. Altogether, our data provide the evidence for an epistatic interaction between the β1 integrin cytoplasmic domain and Rac, and indicate that this anchorage-dependent signaling pathway is crucial for cell growth control.
doi:10.1083/jcb.200111065
PMCID: PMC2173276  PMID: 11980921
integrin; cytodomain; RAC; MAPK; proliferation
6.  Defective Dendrite Elongation but Normal Fertility in Mice Lacking the Rho-Like GTPase Activator Dbl 
Molecular and Cellular Biology  2002;22(9):3140-3148.
Dbl is the prototype of a large family of GDP-GTP exchange factors for small GTPases of the Rho family. In vitro, Dbl is known to activate Rho and Cdc42 and to induce a transformed phenotype. Dbl is specifically expressed in brain and gonads, but its in vivo functions are largely unknown. To assess its role in neurogenesis and gametogenesis, targeted deletion of the murine Dbl gene was accomplished in embryonic stem cells. Dbl-null mice are viable and did not show either decreased reproductive performances or obvious neurological defects. Histological analysis of mutant testis showed normal morphology and unaltered proliferation and survival of spermatogonia. Dbl-null brains indicated a correct disposition of the major neural structures. Analysis of cortical stratification indicated that Dbl is not crucial for neuronal migration. However, in distinct populations of Dbl-null cortical pyramidal neurons, the length of dendrites was significantly reduced, suggesting a role for Dbl in dendrite elongation.
doi:10.1128/MCB.22.9.3140-3148.2002
PMCID: PMC133768  PMID: 11940671

Results 1-6 (6)