Disease relevance of Pik3cg

• We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice [1].
• These data show that PTEN has an important in vivo role in cardiomyocyte hypertrophy and GPCR signaling and identify a function for the PTEN-PI3Kgamma pathway in the modulation of heart muscle contractility [2].
• In humans, p110gamma protein expression is lost in primary colorectal adenocarcinomas from patients and in colon cancer cell lines [3].
• Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)Kgamma [3].
• Peritoneal PI3Kgamma-null macrophages showed a reduced migration toward a wide range of chemotactic stimuli and a severely defective accumulation in a septic peritonitis model [4].

Psychiatry related information on Pik3cg

• Here we show that PS1, a protein involved in familial Alzheimer's disease (FAD), promotes cell survival by activating the PI3K/Akt cell survival signaling [5].

High impact information on Pik3cg

• We find that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110alpha activity [6].
• The G protein-coupled, receptor-activated phosphoinositide 3-kinase gamma (PI3Kgamma) mediates inflammatory responses and negatively controls cardiac contractility by reducing cAMP concentration [7].
• PI3Kalpha mediates the alteration in cell size while PI3Kgamma acts as a negative regulator of cardiac contractility [2].
• PTEN is a 3'-specific phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) phosphatase and functions as a negative regulator of PI3K signaling [8].
• We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target [1].

Chemical compound and disease context of Pik3cg

• Mice lacking PI3Kgamma did not form edema after intradermal injection of adenosine and when challenged by passive systemic anaphylaxis [9].
• Finally, the lethality of the choline-deficient/ethionine-supplemented diet-induced pancreatitis was significantly reduced in mice lacking PI3K gamma [10].
• The mice also exhibited marked decreases in the serum concentrations of FFAs and triglyceride and suppression of insulin-induced PI 3-K activation in adipose tissue, probably due to the associated hyperinsulinemia [11].
• In contrast, beta(2)-AR (but not beta(1)-AR) stimulation elevated the activity of Akt, a powerful survival signal; this effect was fully abolished by inhibiting G(i), G(beta gamma), or phosphoinositide 3 kinase (PI3K) with pertussis toxin, beta ARK-ct (a peptide inhibitor of G(beta gamma)), or LY294002, respectively [12].
• In the present study, we demonstrate that macrophages deficient for PI3K (p85alpha regulatory subunit) are impaired in nitric oxide (NO) production upon lipopolysaccharide and interferon-gamma stimulation and thus vulnerable for intracellular bacterial infection such as Chlamydophila pneumoniae [13].

Biological context of Pik3cg

• Roles of PLC-beta2 and -beta3 and PI3Kgamma in chemoattractant-mediated signal transduction [14].
• Thus, PI3Kgamma regulates thymocyte development, T cell activation, neutrophil migration, and the oxidative burst [15].
• Phosphatidylinositol 3-kinase (PI3K) promotes cell survival and communication by activating its downstream effector Akt kinase [5].
• These data suggest that PI3Kgamma regulates neutrophil chemotaxis primarily by controlling the direction of cell migration and the intracellular colocalization of AKT and F-actin to the leading edge [16].
• It also results in the phosphorylation of PIP2 by the gamma isoform of phosphatidylinositol 3-kinase (PI3Kgamma) to synthesize phosphatidylinositol 3,4,5-trisphosphate [17].

Anatomical context of Pik3cg

• Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration [15].
• We show that PI3Kgamma controls thymocyte survival and activation of mature T cells but has no role in the development or function of B cells [15].
• PI3Kgamma thus relays inflammatory signals through various G(i)-coupled receptors and is central to mast cell function [9].
• PI3Kgamma was found to play a role in angiotensin II-evoked smooth muscle contraction in two crucial, distinct signaling pathways [18].
• PI3Kgamma-/- mice had a selective defect in the number of skin Langerhans cells and in lymph node CD8alpha- DC [19].

Associations of Pik3cg with chemical compounds

• PI3Kgamma-derived PtdIns(3,4,5)P(3) was instrumental for initiating a sustained influx of external Ca(2+) and degranulation [9].
• DOCK2 and PI3Kgamma thus play distinct roles during T and B cell integrin activation and migration [20].
• Adenosine, acting through the A(3) adenosine receptor (A(3)AR) as well as other agonists of G(alphai)-coupled GPCRs, transiently increased PtdIns(3,4,5)P(3) exclusively via PI3Kgamma [9].
• Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma [18].
• Gene-targeted mice were used to evaluate the role of the gamma isoform of phosphoinositide 3-kinase (PI3Kgamma) in dendritic cell (DC) migration and induction of specific T-cell-mediated immune responses [19].
• Identical responses were observed when endogenous chemokine production was induced by TNFalpha; leukocyte emigration was reduced in PI3Kgamma(-/-) mice [21].

Physical interactions of Pik3cg

• In vitro binding experiments revealed that the EphA8 juxtamembrane segment was sufficient for the formation of a stable complex with p110gamma [22].

Regulatory relationships of Pik3cg

• Conversely, PI3Kgamma was necessary to activate protein kinase B/Akt, which, in turn, enhanced L-type Ca(2+) channel-mediated extracellular Ca(2+) entry [18].
• Inhibition of PI 3-kinase decreased the LPS-induced transcriptional activity of NF-kappaB, but it had no effect on the nuclear DNA binding activity of NF-kappaB [23].
• When platelets from mice lacking the G protein-activated PI3Kgamma isoform were stimulated with ADP, aggregation was impaired [24].
• Occludin was hyperphosphorylated by IL-1beta treatment and was inhibited by treatment with a PI3-kinase inhibitor [25].
• Furthermore, CSF-1 failed to stimulate PI 3-kinase activity in resident peritoneal macrophages, a population of macrophages with poor proliferative capacity [26].

Other interactions of Pik3cg

• This effect was partially dependent on the PI3K subunits p85alpha and p110gamma [27].
• In response to angiotensin II, PI3Kgamma was required for the activation of Rac and the subsequent triggering of ROS production [18].
• Infusion with p110beta/p85alpha or p110gamma PI3K in the presence of PI(4,5)P2 also restored I(Ca,L) density to wild-type levels [28].
• Cutting edge: T cell development requires the combined activities of the p110gamma and p110delta catalytic isoforms of phosphatidylinositol 3-kinase [29].
• Among neutrophils that did accumulate in the lungs of the PI3-Kgamma(-/-) mice after endotoxin administration, activation of NF-kappaB and expression of proinflammatory cytokines was diminished compared with levels present in lung neutrophils from PI3-Kgamma(+/+) mice [30].
• These observations identify p110delta as a key therapeutic target among PI3K isoforms for allergy- and mast cell-related diseases [31].

Analytical, diagnostic and therapeutic context of Pik3cg

• We show that, in PI3KgammaKD/KD hearts, cAMP levels are normal and that PI3Kgamma-deficient mice but not PI3KgammaKD/KD mice develop dramatic myocardial damage after chronic pressure overload induced by transverse aortic constriction (TAC) [7].
• These data indicate that PI3Kgamma is a key transducer of the intracellular signals that are evoked by angiotensin II and suggest that blocking PI3Kgamma function might be exploited to improve therapeutic intervention on hypertension [18].
• Nevertheless, only microinjection of anti-p110alpha (and not p110gamma) antibody inhibited both insulin- and Q209L-Galphaq-induced GLUT4 translocation, suggesting that the metabolic effects induced by Q209L-Galphaq are dependent on the p110alpha subunit of PI3-kinase [32].
• Using E13 mouse SMG organ cultures, we showed that inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase), wortmannin and LY294002, substantially inhibited branching morphogenesis in SMG [33].
• Experiments with adoptive transfer of bone marrow showed that PI3Kgamma in eosinophils but not in non-bone marrow-derived cells was required for their accumulation [34].

References