Journal
EMBO JOURNAL
Volume 31, Issue 14, Pages 3118-3129Publisher
WILEY
DOI: 10.1038/emboj.2012.167
Keywords
neutrophil; PI3K; PLC beta; Ras; RasGRP4
Categories
Funding
- BBSRC [BB/D013593/1]
- British Lung Foundation
- BBSRC [BB/D013593/1, BBS/E/B/0000C238, BBS/E/B/000C0411] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D013593/1, BBS/E/B/000C0411, C20177, BBS/E/B/0000C238] Funding Source: researchfish
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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. The EMBO Journal (2012) 31, 3118-3129. doi: 10.1038/emboj.2012.167; Published online 22 June 2012
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