Disease relevance of Pik3r1

• We conclude that acidosis accelerates protein degradation by impairing insulin signaling through PI3K in muscle cells [1].
• To establish that the PI3K pathway can regulate protein degradation in muscle, we measured proteolysis in cells after inhibition of PI3K activity with LY-294002 or infection with an adenovirus encoding a dominant negative PI3K p85alpha-subunit [1].
• Taken together, these results suggest that PI 3-kinase may act as a negative regulator of MMP-9 expression in C6 glioma cells [2].
• These results indicate that tyrosine phosphorylation of PLC-gamma 1, GAP, and PI-3-kinase are specific responses for VSMC hyperplasia but not thromboxane-stimulated hypertrophy [3].
• METHODS: PI3K activation was evaluated in isolated rat hepatocytes preconditioned by 10-minute hypoxia followed by 10-minute reoxygenation [4].

High impact information on Pik3r1

• We studied five downstream effectors of growth factor receptors--Ras, Raf, Src, phosphoinositide 3-kinase (PI 3-kinase), and Akt (PKB)--for their abilities to block apoptosis [5].
• Thus, the PI 3-kinase/Akt (PKB) signaling pathway transduces a survival signal that ultimately blocks Ced3/ICE-like activity [5].
• In contrast, inhibition of PI 3-kinase accelerated apoptosis, and an activated form of the serine/threonine kinase Akt, a downstream effector of PI 3-kinase, blocked apoptosis [5].
• Phosphoinositide 3 kinase enhancer (PIKE) is a recently identified nuclear GTPase that activates nuclear phosphoinositide 3-kinase (PI3 kinase) [6].
• Additionally, ICV administration of leptin increased hypothalamic phosphatidylinositol 3-kinase (PI3K) and PDE3B activities and decreased cyclic AMP (cAMP) concentration [7].

Chemical compound and disease context of Pik3r1

• In the cells treated with CGS21680, PI3K activation was prevented either by inhibiting adenylate cyclase and PKA with, respectively, 2,5-dideoxyadenosine and H89 or by blocking Galphai-protein and Src tyrosine kinase with, respectively, pertussis toxin and PP2 [4].
• PI3K (phosphoinositide 3-kinase) activity is involved in Ang (angiotensin) II-stimulated VSMC (vascular smooth muscle cell) growth and hypertrophy [8].
• A PI3K Pathway Mediates Hair Cell Survival and Opposes Gentamicin Toxicity in Neonatal Rat Organ of Corti [9].
• Down-regulation of PTEN by sodium orthovanadate inhibits ASK1 activation via PI3-K/Akt during cerebral ischemia in rat hippocampus [10].
• Pertussis toxin, suramin, reactive blue 2, PPADS, DPCPX and inhibitors of Protein Kinase C, Protein Kinase A and PI3 kinase significantly reduced the upregulation of egr-1 by exposure to extracellular ATP [11].

Biological context of Pik3r1

• METHODS: Immunodetection was used to compare the expression and tyrosine phosphorylation state of PLC gamma 1, EGFR, phosphatidylinositol 3-kinase (PI 3-kinase), ras guanosine triphosphatase activating protein (GAP), and src homologous collagen-like protein (SHC) in the postnatal rat intestine [12].
• In the absence of extracellular Ca2+, NMDA was unable to prevent apoptosis or to phosphorylate IRS-1 and activate PI 3-kinase [13].
• Finally, beta PDGF receptors that have tyrosine-to-phenylalanine point mutations at positions 708, 719, 977 and 989 did not associate with either PI 3-kinase or PLC-gamma 1 [14].
• We also demonstrated that loss of cell-cell adhesion and the increase in cell motility induced by gastrin required the activation of JAK2 and the PI 3-kinase [15].
• Our results suggest that the interaction between cAMP-dependent and IGF-I-dependent pathways leads to an augmentation of cell proliferation, which is mediated, at least in part, through the MAP kinase and PI 3-kinase signalling pathways [16].

Anatomical context of Pik3r1

• We have recently shown that the insulin-like effects of growth hormone (GH) in adipocytes can be inhibited by the selective PI 3-kinase inhibitor wortmannin (Ridderstråle, M., and Tornqvist, H. (1994) Biochem. Biophys. Res. Commun. 203, 306-310), suggesting a similar role for PI 3-kinase in GH action [17].
• Furthermore, two structurally distinct inhibitors of PI3K (wortmannin and LY294002) inhibited NE uptake in intact as well as digitonin-permeabilized PC12 cells, but had no effect on calcium-evoked NE secretion [18].
• This contrasts with the requirements for mitogenesis for epithelial and fibroblast cell lines, in which the association of PI 3-kinase with the beta PDGF receptor is essential [14].
• Our results indicate that rab3 and PI3K positively and coordinately regulate NE uptake in PC12 neuroendocrine cells at least in part by stimulating the secretory vesicle uptake step [18].
• These data suggest that BDNF modulation of high-frequency transmission is independent of protein synthesis but requires MAPK and PI3K and yet another signaling pathway to act together in the hippocampus [19].

Associations of Pik3r1 with chemical compounds

• Inhibition of apoptosis by NMDA was blocked by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY294002, but it was unaffected by the mitogen-activated protein kinase kinase inhibitor PD 98059 [13].
• These data demonstrate that the neurotrophic action of NMDA and its inhibition by ethanol are mediated by alterations in the activity of a PI 3-kinase-dependent antiapoptotic signaling pathway [13].
• LY294002, a PI 3-kinase inhibitor, strongly depressed IGF-I-dependent DNA synthesis after pretreatment with and without TSH or dibutyryl cAMP [16].
• In this study, we found that 2-(3-pyridyl)-1-azabicyclo[3.2.2]nonane (TC-1698), a novel alpha7-selective agonist, exerts neuroprotective effects via activation of the JAK2/PI-3K cascade, which can be neutralized through activation of the angiotensin II (Ang II) AT(2) receptor [20].
• We have recently provided evidence for nicotine-induced complex formation between the alpha7 nicotinic acetylcholine receptor (nAChR) and the tyrosine-phosphorylated enzyme Janus kinase 2 (JAK2) that results in subsequent activation of phosphatidylinositol-3-kinase (PI-3-K) and Akt [20].

Physical interactions of Pik3r1

• Our data suggest that GH-induced tyrosine phosphorylation of IRS-1 and the subsequent docking of PI 3-kinase are important postreceptor events in GH action [17].
• We report that phosphatidylinositol 3'-kinase (PI3K) binds to a unique site in the carboxy tail of murine Flt3/Flk2 [21].
• In addition, both anti-Grb2 and anti-PI3-K antibodies coprecipitated Shp2 in response to BDNF [22].
• PI3-kinase p85 was co-precipitated with NR2B after transient global ischemia [23].
• The Btk PH domain can bind in vitro to several lipid end products of the phosphatidylinositol 3-kinase (PI 3-kinase) family including phosphatidylinositol 3,4,5-trisphosphate [24].

Enzymatic interactions of Pik3r1

• Insulin receptor substrate-1 (IRS-1) is tyrosine-phosphorylated in response to insulin resulting in association with and activation of phosphatidylinositol 3-kinase (PI 3-kinase), thereby initiating some of the effects of insulin [17].

Co-localisations of Pik3r1

• Furthermore, PI3K also co-localized with p-PKB to the same site in the epithelium as determined by fluorescence microscopy, consistent with their localization at the ES [25].

Regulatory relationships of Pik3r1

• These results support the main hypothesis that states that JAK2 plays a central role in the nicotinic alpha7 receptor-induced activation of the JAK2-PI-3K cascade in PC12 cells, which ultimately contribute to nAChR-mediated neuroprotection [20].
• In conclusion, G17 promotes AR42J cell survival through the induction of Akt via PI 3-kinase and SB-203580-sensitive kinase activities [26].
• Here, we report that PI 3-kinase inhibits MMP-9 expression induced by either IL-1 or TNF-alpha in rat C6 glioma cells [2].
• In contrast, there was a high level of IRS-2 expression and insulin-stimulated tyrosyl phosphorylation as early as embryonic day 15 with robust PI3K binding and activation, which may enhance hepatocyte survival during the rapid growth phase of the liver [27].
• We examined how BDNF activates PI3-K in cultured cerebral cortical neurons [28].

Other interactions of Pik3r1

• These results, together with the effects of pharmacological inhibitors, support the notion that there are common cytosolic signaling pathways for two separate groups of guidance cues, one of which requires coactivation of PLC-gamma and PI3-kinase pathways [29].
• Stimulation with 23 nM GH increased the PI 3-kinase activity associated with IRS1 4-fold [17].
• RESULTS: Receptors lacking the kinase-insert domain did not associate with either phosphatidylinositol 3-kinase (PI 3-kinase) or Ras GTPase-activating protein (Ras-GAP) in PC12 cells [14].
• In addition, we found that NO produces c-Src/PI3K- and PKG-dependent activation of ERK 1/2 [30].
• The repressive effect of TGF-alpha on caveolin-1 expression was MAP kinase-independent and partly mediated through the PI3-kinase pathway [31].

Analytical, diagnostic and therapeutic context of Pik3r1

• Using zymography and semi-quantitative RT-PCR analysis, we showed that treatment of C6 cells with wortmannin, an inhibitor of PI 3-kinase activity, potentiated the expression of MMP-9 induced by both cytokines [2].
• In euglycemic clamp studies, insulin infusion greatly increased tyrosine phosphorylation of IRbeta- and IRS-2-associated PI 3-kinase activity in the aorta of lean rats, but only slight increases were observed in obese rats [32].
• By regulating PKC-/delta-dependent signals, PI3K can play a key role in the development of hepatic tolerance to hypoxia/reperfusion [4].
• Immunoprecipitation with anti-p85 antibodies and phosphotyrosine immunoblotting revealed no tyrosine phosphorylation of PI 3-kinase, but demonstrated co-precipitation of tyrosine-phosphorylated IRS-1, as well as another phosphotyrosine protein of approximately 135-140 kDa [33].
• We also suggest that after treatment with vanadate, MembPTK is activated by autophosphorylation and interacts with PI 3-kinase [34].

References