P-Rex1 Regulates Neutrophil Function

Welch, Heidi; Condliffe, Alison M.; Milne, Louise; Ferguson, Gail; Hill, Kirsti; Webb, Louise M. C.; Okkenhaug, Klaus; Coadwell, W. John; Andrews, Simon; Thelen, Marcus; Jones, Gareth E.; Hawkins, Phillip T.; Stephens, Len R.

doi:10.1016/j.cub.2005.09.050

Cited by 154 publications

(197 citation statements)

References 27 publications

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“…5 and 6), both activation of phosphatidylinositol-specific PLC and PI3K␥ are normal in Hck/Fgrdeficient neutrophils. Consistent with the evidence that NADPH oxidase activation requires the synergistic action of Vav1, P-Rex1, and DOCK2 GEFs (55,63,64,66), in assay conditions revealing defective fMLP-induced superoxide anion generation by hck Ϫ/Ϫ fgr Ϫ/Ϫ neutrophils, a PI3K␥ inhibitor markedly reduced this response in WT neutrophils and totally suppressed it in KO cells (Fig. 7).…”

Section: Discussionsupporting

confidence: 86%

“…The GTP-bound, active form of Rac is generated by GEFs that catalyze the release of GDP from inactive Rac. Vav1 and P-Rex1 are two well-established GEFs involved in Rac2 activation (55,63,64). Importantly, deficiency of Vav1 and P-Rex-1 results in a very similar neutrophil phenotype consisting in a selective defect in fMLP-induced respiratory burst, but in a minor impairment of fMLP-induced chemotaxis.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, defective release of reactive oxygen molecules in response to chemoattractants may result in reduced activation of endothelial cells and the consequent recruitment of neutrophils. In this context, it is worth noting that also neutrophils from P-Rex1 Ϫ/Ϫ mice, which display only a mild alteration in their migratory ability in vitro, are recruited to a significantly lower extent in sites of inflammation in vivo (63). Our findings that hck Ϫ/Ϫ fgr Ϫ/Ϫ PMNs chemotact normally through 3-m pore size filters, but fail to go through narrower 1-m pores, raise the intriguing possibility that Src family kinases regulate cell deformability and/or strength of leading edge protrusion through the endothelial cell layer.…”

Section: Discussionmentioning

confidence: 99%

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The Src Family Kinases Hck and Fgr Regulate Neutrophil Responses to N-Formyl-Methionyl-Leucyl-Phenylalanine

Fumagalli

Zhang

Baruzzi

et al. 2007

The Journal of Immunology

106

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The chemotactic peptide formyl-methionyl-leucyl-phenilalanine (fMLP) triggers intracellular protein tyrosine phosphorylation leading to neutrophil activation. Deficiency of the Src family kinases Hck and Fgr have previously been found to regulate fMLP-induced degranulation. In this study, we further investigate fMLP signaling in hck−/−fgr−/− neutrophils and find that they fail to activate a respiratory burst and display reduced F-actin polymerization in response to fMLP. Additionally, albeit migration of both hck−/−fgr−/− mouse neutrophils and human neutrophils incubated with the Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) through 3-μm pore size Transwells was normal, deficiency, or inhibition, of Src kinases resulted in a failure of neutrophils to migrate through 1-μm pore size Transwells. Among MAPKs, phosphorylation of ERK1/2 was not different, phosphorylation of p38 was only partially affected, and phosphorylation of JNK was markedly decreased in fMLP-stimulated hck−/−fgr−/− neutrophils and in human neutrophils incubated with PP2. An increase in intracellular Ca2+ concentration and phosphorylation of Akt/PKB occurred normally in fMLP-stimulated hck−/−fgr−/− neutrophils, indicating that activation of both phosphoinositide-specific phospholipase C and PI3K is independent of Hck and Fgr. In contrast, phosphorylation of the Rho/Rac guanine nucleotide exchange factor Vav1 and the Rac target p21-activated kinases were markedly reduced in both hck−/−fgr−/− neutrophils and human neutrophils incubated with a PP2. Consistent with these findings, PP2 inhibited Rac2 activation in human neutrophils. We suggest that Hck and Fgr act within a signaling pathway triggered by fMLP receptors that involves Vav1 and p21-activated kinases, leading to respiratory burst and F-actin polymerization.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Src Family Kinases Hck and Fgr Regulate Neutrophil Responses to N-Formyl-Methionyl-Leucyl-Phenylalanine

Fumagalli

Zhang

Baruzzi

et al. 2007

The Journal of Immunology

106

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“…S3E) (9). Although the motor behavior of Prex1 −/− /Prex2 −/− double-knockout mice is more impaired than that of Prex2 −/− mice (21), Prex1 −/− mice displayed normal motor coordination and balance with the rotarod ( To characterize sensory deficits, we measured the degree of prepulse inhibition and found no significant differences between genotypes (Fig.…”

Section: Significancementioning

confidence: 96%

“…This gene is known to be highly expressed in neutrophils and in the mouse brain (8). Mice with the Prex1 gene deleted (Prex1 −/− ) exhibited Racdependent mild neutrophilia (9) and melanoblast migration defects (10). P-Rex1 influences neuronal cell motility (11) and neurite elongation (12) by regulating actin dynamics specifically at the growth cone.…”

mentioning

confidence: 99%

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Chai

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1α (protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs. Several studies have documented impairments of social recognition [e.g., such as deficits in recognizing unfamiliar faces (2)] and in behavioral flexibility [e.g., impaired reversal learning and difficulties in error correction (3, 4)] in autistic people. However, the neurobiological mechanism responsible for the symptoms of ASDs, and especially for the deficit in social recognition, is little known.Recent genetic studies have identified a large number of candidate genes for ASDs (5, 6), including many that code for synaptic proteins. Synaptic dysfunction may play a critical role in ASDs (7).Here we have identified a new autism-associated gene, Prex1, that codes for P-Rex1 (phosphatidylinositol-3,4,5-trisphosphatedependent Rac exchange factor 1), a Rac-specific Rho GTPase guanine nucleotide exchange factor (GEF). This gene is known to be highly expressed in neutrophils and in the mouse brain (8). Mice with the Prex1 gene deleted (Prex1 −/− ) exhibited Racdependent mild neutrophilia (9) and melanoblast migration defects (10). P-Rex1 influences neuronal cell motility (11) and neurite elongation (12) by regulating actin dynamics specifically at the growth cone. However, the role of P-Rex1 in regulating synaptic function and related behaviors remains unknown.In addition to identifying an association between PREX1 and autism in humans, we demonstrate that genetic disruption of P-Rex1 in mice leads to autism-like social behavior and to other features known to be associated with ASDs. Electrophysiological studies revealed a specific impairment of NMDA receptor (NMDAR)-dependent long-term depression (LTD) at Schaffer collateralcornus ammonis region 1 (SC-CA1) synapses. Furthermore, these defects were associated with dysfunction in NMDA-induced AMPA receptor (AMPAR) endocytosis, because of defective PP1α (serine/threonine protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling, and correcting the latter rectified the social recognition defici...

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Genomic associations with bill length and disease reveal drift and selection across island bird populations

et al. 2018

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Island species provide excellent models for investigating how selection and drift operate in wild populations, and for determining how these processes act to influence local adaptation and speciation. Here, we examine the role of selection and drift in shaping genomic and phenotypic variation across recently separated populations of Berthelot's pipit (Anthus berthelotii), a passerine bird endemic to three archipelagos in the Atlantic. We first characterized genetic diversity and population structuring that supported previous inferences of a history of recent colonizations and bottlenecks. We then tested for regions of the genome associated with the ecologically important traits of bill length and malaria infection, both of which vary substantially across populations in this species. We identified a SNP associated with variation in bill length among individuals, islands, and archipelagos; patterns of variation at this SNP suggest that both phenotypic and genotypic variation in bill length is largely shaped by founder effects. Malaria was associated with SNPs near/within genes involved in the immune response, but this relationship was not consistent among archipelagos, supporting the view that disease resistance is complex and rapidly evolving. Although we found little evidence for divergent selection at candidate loci for bill length and malaria resistance, genome scan analyses pointed to several genes related to immunity and metabolism as having important roles in divergence and adaptation. Our findings highlight the utility and challenges involved with combining association mapping and population genetic analysis in nonequilibrium populations, to disentangle the effects of drift and selection on shaping genotypes and phenotypes.

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P-Rex1 Regulates Neutrophil Function

Cited by 154 publications

References 27 publications

The Src Family Kinases Hck and Fgr Regulate Neutrophil Responses to N-Formyl-Methionyl-Leucyl-Phenylalanine

The Src Family Kinases Hck and Fgr Regulate Neutrophil Responses to N-Formyl-Methionyl-Leucyl-Phenylalanine

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Genomic associations with bill length and disease reveal drift and selection across island bird populations

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