Journal
NATURE CELL BIOLOGY
Volume 8, Issue 11, Pages 1303-1309Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1494
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Funding
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000M090, C19943, BB/D013593/1, C20177] Funding Source: Medline
- Medical Research Council [G120/825, G117/424] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
- BBSRC [BB/D013593/1] Funding Source: UKRI
- MRC [G120/825, G117/424] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [C20177, BB/D013593/1, C19943, BBS/E/B/0000M090] Funding Source: researchfish
- Medical Research Council [G117/424, G120/825] Funding Source: researchfish
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Through their ability to regulate production of the key lipid messenger PtdIns(3,4,5)P-3, the class I phosphatidylinositol-3-OH kinases (PI(3)Ks) support many critical cell responses(1,2). They, in turn, can be regulated by cell-surface receptors through signals acting on either their adaptor subunits (for example, through phosphotyrosine or G beta gamma s) or their catalytic subunits (for example, through GTP-Ras). The relative significance of these controlling inputs is undefined in vivo. Here, we have studied the roles of G beta gamma s, the adaptor p101, Ras and the Ras binding domain (RBD) in the control of the class I PI(3)K, PI(3)K gamma, in mouse neutrophils. Loss of p101 leads to major reductions in the accumulation of PtdIns(3,4,5)P-3, activation of protein kinase B (PKB) and in migration towards G-protein activating ligands in vitro, and to an aseptically inflamed peritoneum in vivo. Loss of sensitivity of PI(3)K gamma to Ras unexpectedly caused similar reductions, but additionally caused a substantial loss in production of reactive oxygen species (ROS). We conclude that G beta gamma s, p101 and the Ras-RBD interaction all have important roles in the regulation of PI(3)K gamma in vivo and that they can simultaneously, but differentially, control distinct PI(3)K gamma effectors.
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