GPCR activation of Ras and PI3K gamma in neutrophils depends on PLC beta 2/beta 3 and the RasGEF RasGRP4
2012
Niewczas , Izabella(collaborateur) (Babraham Biosci Technol Ltd, Cambridge(Royaume Uni). Babraham Biosci Technol Ltd) | Davidson , Keith(collaborateur) (Babraham Institute, Cambridge CB22 3AT(Royaume Uni). Inositide Lab) | Guillou , Hervé(collaborateur) (INRA , St-Martin-Du-Touch (France). UMR 1331 Toxicologie Alimentaire) | Pan , Dingxin(collaborateur) (Babraham Institute, Cambridge CB22 3AT(Royaume Uni). Inositide Lab) | Clark , Jonathan(collaborateur) (Babraham Biosci Technol Ltd, Cambridge(Royaume Uni). Babraham Biosci Technol Ltd) | Hawkins , Phillip T(collaborateur) (Babraham Institute, Cambridge CB22 3AT(Royaume Uni). Inositide Lab) | Stephens , Len(auteur de correspondance) (Babraham Institute, Cambridge CB22 3AT(Royaume Uni). Inositide Lab)
The molecular mechanisms by which receptors regulate the Ras Binding Domains of the PIP3-generating, class I PI3Ks remain poorly understood, despite their importance in a range of biological settings, including tumorigenesis, activation of neutrophils by pro-inflammatory mediators, chemotaxis of Dictyostelium and cell growth in Drosophila. We provide evidence that G protein-coupled receptors (GPCRs) can stimulate PLC beta 2/beta 3 and diacylglycerol-dependent activation of the RasGEF, RasGRP4 in neutrophils. The genetic loss of RasGRP4 phenocopies knock-in of a Ras-insensitive version of PI3K gamma in its effects on PI3K gamma-dependent PIP3 accumulation, PKB activation, chemokinesis and reactive oxygen species (ROS) formation. These results establish a new mechanism by which GPCRs can stimulate Ras, and the broadly important principle that PLCs can control activation of class I PI3Ks.
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