ArticleProceedings of the National Academy of Sciences of the United States of America2007
Negative feedback regulation of Rac in leukocytes from mice expressing a constitutively active phosphatidylinositol 3-kinase gamma.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 58 citations in OpenAlex.
- Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma.Science translational medicine · 2023Article
- Function, Regulation and Biological Roles of PI3Kγ Variants.Biomolecules · 2019Review
- Cross-talk between Rho GTPases and PI3K in the neutrophil.Small GTPases · 2019Review
- Excess active P13K rescues huntingtin-mediated neuronal cell death but has no effect on axonal transport defects.Apoptosis : an international journal on programmed cell death · 2019Article
- Salmonella Typhimurium effector SseI inhibits chemotaxis and increases host cell survival by deamidation of heterotrimeric Gi proteins.PLoS pathogens · 2018Article
- A module for Rac temporal signal integration revealed with optogenetics.The Journal of cell biology · 2017Article
- PI3Kδ promotes CD4(+) T-cell interactions with antigen-presenting cells by increasing LFA-1 binding to ICAM-1.Immunology and cell biology · 2016Article
- Molecular control of PtdIns(3,4,5)P3 signaling in neutrophils.EMBO reports · 2015Review
- Crossroads of PI3K and Rac pathways.Small GTPases · 2015Review
- Molecular determinants of PI3Kγ-mediated activation downstream of G-protein-coupled receptors (GPCRs).Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- PI3-kinase γ promotes Rap1a-mediated activation of myeloid cell integrin α4β1, leading to tumor inflammation and growth.PloS one · 2013Article
- Signaling by the phosphoinositide 3-kinase family in immune cells.Annual review of immunology · 2013Review
- Differential roles for the p101 and p84 regulatory subunits of PI3Kγ in tumor growth and metastasis.Oncogene · 2012Article
- Endogenous migration modulators as parent compounds for the development of novel cardiovascular and anti-inflammatory drugs.British journal of pharmacology · 2012Review
- The Therapeutic Potential for PI3K Inhibitors in Autoimmune Rheumatic Diseases.The open rheumatology journal · 2012Article
- A mathematical model of CR3/TLR2 crosstalk in the context of Francisella tularensis infection.PLoS computational biology · 2012Article
- Silencer of death domains (SODD) inhibits skeletal muscle and kidney enriched inositol 5-phosphatase (SKIP) and regulates phosphoinositide 3-kinase (PI3K)/Akt signaling to the actin cytoskeleton.The Journal of biological chemistry · 2011Article
- Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression.Cancer cell · 2011Article
- Prediction of sphingosine 1-phosphate-stimulated endothelial cell migration rates using biochemical measurements.Annals of biomedical engineering · 2010Article
- PI3Kgamma-dependent signaling in mouse olfactory receptor neurons.Chemical senses · 2010Article
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Polarization of chemotaxing cells depends on positive feedback loops that amplify shallow gradients of chemoattractants into sharp intracellular responses. In particular, reciprocal activation of phosphatidylinositol 3-kinases (PI3Ks) and small GTPases like Rac leads to accumulation, at the leading edge, of the PI3K product phosphatidylinositol 3,4,5-trisphosphate (PIP3). Mice carrying a "knockin" allele of the G protein-coupled receptor (GPCR)-activated PI3Kgamma, encoding a plasma membrane-targeted protein appeared normal, but their leukocytes showed GPCR-uncoupled PIP3 accumulation. In vivo, the mutation increased proliferation and decreased apoptosis, leading to leukocytosis and delayed resolution of inflammation in wound healing. Mutant leukocytes showed significantly impaired directional cell migration in response to chemoattractants. Stimulated mutant macrophages did not polarize PIP3 and showed a shortened Rac activation because of enhanced PI3K-dependent activation of RacGAPs. Together with the finding that chemoattractants stimulate a PIP3-dependent GAP activation in wild-type macrophages, these results identify a molecular mechanism involving PI3K- and RacGAP-dependent negative control of Rac that limits and fine-tunes feedback loops promoting cell polarization and directional motility.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.