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Gene Review

Pik3r1  -  phosphoinositide-3-kinase, regulatory...

Rattus norvegicus

Synonyms: PI3-kinase regulatory subunit alpha, PI3-kinase subunit p85-alpha, PI3K regulatory subunit alpha, Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha, Phosphatidylinositol 3-kinase regulatory subunit alpha, ...
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Disease relevance of Pik3r1


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


Biological context of Pik3r1


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


Enzymatic interactions of Pik3r1


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


  1. Acidosis impairs insulin receptor substrate-1-associated phosphoinositide 3-kinase signaling in muscle cells: consequences on proteolysis. Franch, H.A., Raissi, S., Wang, X., Zheng, B., Bailey, J.L., Price, S.R. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  2. Induced expression of MMP-9 in C6 glioma cells is inhibited by PDGF via a PI 3-kinase-dependent pathway. Estève, P.O., Robledo, O., Potworowski, E.F., St-Pierre, Y. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  3. Patterns of tyrosine phosphorylation differ in vascular hypertrophy and hyperplasia. Ali, S., Dorn, G.W. Am. J. Physiol. (1994) [Pubmed]
  4. Role of phosphatidylinositol 3-kinase in the development of hepatocyte preconditioning. Carini, R., Grazia De Cesaris, M., Splendore, R., Baldanzi, G., Nitti, M.P., Alchera, E., Filigheddu, N., Domenicotti, C., Pronzato, M.A., Graziani, A., Albano, E. Gastroenterology (2004) [Pubmed]
  5. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Kennedy, S.G., Wagner, A.J., Conzen, S.D., Jordán, J., Bellacosa, A., Tsichlis, P.N., Hay, N. Genes Dev. (1997) [Pubmed]
  6. PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis. Rong, R., Ahn, J.Y., Huang, H., Nagata, E., Kalman, D., Kapp, J.A., Tu, J., Worley, P.F., Snyder, S.H., Ye, K. Nat. Neurosci. (2003) [Pubmed]
  7. A phosphatidylinositol 3-kinase phosphodiesterase 3B-cyclic AMP pathway in hypothalamic action of leptin on feeding. Zhao, A.Z., Huan, J.N., Gupta, S., Pal, R., Sahu, A. Nat. Neurosci. (2002) [Pubmed]
  8. Angiotensin II stimulates phosphorylation of an ectodomain-truncated platelet-derived growth factor receptor-beta and its binding to class IA PI3K in vascular smooth muscle cells. Gao, B.B., Hansen, H., Chen, H.C., Feener, E.P. Biochem. J. (2006) [Pubmed]
  9. A PI3K Pathway Mediates Hair Cell Survival and Opposes Gentamicin Toxicity in Neonatal Rat Organ of Corti. Chung, W.H., Pak, K., Lin, B., Webster, N., Ryan, A.F. J. Assoc. Res. Otolaryngol. (2006) [Pubmed]
  10. Down-regulation of PTEN by sodium orthovanadate inhibits ASK1 activation via PI3-K/Akt during cerebral ischemia in rat hippocampus. Wu, D.N., Pei, D.S., Wang, Q., Zhang, G.Y. Neurosci. Lett. (2006) [Pubmed]
  11. Regulation of expression of early growth response transcription factors in rat primary cortical neurons by extracellular ATP. McKee, S.C., Thompson, C.S., Sabourin, L.A., Hakim, A.M. Brain Res. (2006) [Pubmed]
  12. Ontogenic regulation of phospholipase C-gamma 1 activity and expression in the rat small intestine. Polk, D.B. Gastroenterology (1994) [Pubmed]
  13. N-Methyl-D-aspartate inhibits apoptosis through activation of phosphatidylinositol 3-kinase in cerebellar granule neurons. A role for insulin receptor substrate-1 in the neurotrophic action of n-methyl-D-aspartate and its inhibition by ethanol. Zhang, F.X., Rubin, R., Rooney, T.A. J. Biol. Chem. (1998) [Pubmed]
  14. Beta PDGF receptor mutants defective for mitogenesis promote neurite outgrowth in PC12 cells. Vetter, M.L., Bishop, J.M. Curr. Biol. (1995) [Pubmed]
  15. Involvement of JAK2 upstream of the PI 3-kinase in cell-cell adhesion regulation by gastrin. Ferrand, A., Kowalski-Chauvel, A., Bertrand, C., Pradayrol, L., Fourmy, D., Dufresne, M., Seva, C. Exp. Cell Res. (2004) [Pubmed]
  16. Signalling pathways of insulin-like growth factor-I that are augmented by cAMP in FRTL-5 cells. Ariga, M., Nedachi, T., Akahori, M., Sakamoto, H., Ito, Y., Hakuno, F., Takahashi, S. Biochem. J. (2000) [Pubmed]
  17. Growth hormone stimulates the tyrosine phosphorylation of the insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase in primary adipocytes. Ridderstråle, M., Degerman, E., Tornqvist, H. J. Biol. Chem. (1995) [Pubmed]
  18. Coordinate regulation of catecholamine uptake by rab3 and phosphoinositide 3-kinase. Francis, S.C., Sunshine, C., Kirk, K.L. J. Biol. Chem. (2002) [Pubmed]
  19. Signaling mechanisms mediating BDNF modulation of synaptic plasticity in the hippocampus. Gottschalk, W.A., Jiang, H., Tartaglia, N., Feng, L., Figurov, A., Lu, B. Learn. Mem. (1999) [Pubmed]
  20. The neuroprotective effect of 2-(3-pyridyl)-1-azabicyclo[3.2.2]nonane (TC-1698), a novel alpha7 ligand, is prevented through angiotensin II activation of a tyrosine phosphatase. Marrero, M.B., Papke, R.L., Bhatti, B.S., Shaw, S., Bencherif, M. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  21. Phosphatidylinositol-3' kinase is not required for mitogenesis or internalization of the Flt3/Flk2 receptor tyrosine kinase. Beslu, N., LaRose, J., Casteran, N., Birnbaum, D., Lecocq, E., Dubreuil, P., Rottapel, R. J. Biol. Chem. (1996) [Pubmed]
  22. Brain-derived neurotrophic factor stimulates interactions of Shp2 with phosphatidylinositol 3-kinase and Grb2 in cultured cerebral cortical neurons. Yamada, M., Ohnishi, H., Sano, S., Araki, T., Nakatani, A., Ikeuchi, T., Hatanaka, H. J. Neurochem. (1999) [Pubmed]
  23. Transient ischemia enhances tyrosine phosphorylation and binding of the NMDA receptor to the Src homology 2 domain of phosphatidylinositol 3-kinase in the rat hippocampus. Takagi, N., Sasakawa, K., Besshoh, S., Miyake-Takagi, K., Takeo, S. J. Neurochem. (2003) [Pubmed]
  24. Phosphatidylinositol 3-kinase-gamma activates Bruton's tyrosine kinase in concert with Src family kinases. Li, Z., Wahl, M.I., Eguinoa, A., Stephens, L.R., Hawkins, P.T., Witte, O.N. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  25. Sertoli-germ cell anchoring junction dynamics in the testis are regulated by an interplay of lipid and protein kinases. Siu, M.K., Wong, C.H., Lee, W.M., Cheng, C.Y. J. Biol. Chem. (2005) [Pubmed]
  26. Molecular mechanisms for the antiapoptotic action of gastrin. Todisco, A., Ramamoorthy, S., Witham, T., Pausawasdi, N., Srinivasan, S., Dickinson, C.J., Askari, F.K., Krametter, D. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  27. Insulin signaling through insulin receptor substrate 1 and 2 in normal liver development. Khamzina, L., Gruppuso, P.A., Wands, J.R. Gastroenterology (2003) [Pubmed]
  28. Insulin receptor substrate (IRS)-1 and IRS-2 are tyrosine-phosphorylated and associated with phosphatidylinositol 3-kinase in response to brain-derived neurotrophic factor in cultured cerebral cortical neurons. Yamada, M., Ohnishi, H., Sano, S., Nakatani, A., Ikeuchi, T., Hatanaka, H. J. Biol. Chem. (1997) [Pubmed]
  29. Phospholipase C-gamma and phosphoinositide 3-kinase mediate cytoplasmic signaling in nerve growth cone guidance. Ming, G., Song, H., Berninger, B., Inagaki, N., Tessier-Lavigne, M., Poo, M. Neuron (1999) [Pubmed]
  30. nitric oxide triggers the phosphatidylinositol 3-kinase/Akt survival pathway in insulin-producing RINm5F cells by arousing Src to activate insulin receptor substrate-1. Tejedo, J.R., Cahuana, G.M., Ramírez, R., Esbert, M., Jiménez, J., Sobrino, F., Bedoya, F.J. Endocrinology (2004) [Pubmed]
  31. Caveolin and GLT-1 gene expression is reciprocally regulated in primary astrocytes: association of GLT-1 with non-caveolar lipid rafts. Zschocke, J., Bayatti, N., Behl, C. Glia (2005) [Pubmed]
  32. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. Jiang, Z.Y., Lin, Y.W., Clemont, A., Feener, E.P., Hein, K.D., Igarashi, M., Yamauchi, T., White, M.F., King, G.L. J. Clin. Invest. (1999) [Pubmed]
  33. Insulin stimulation of phosphatidylinositol 3-kinase activity and association with insulin receptor substrate 1 in liver and muscle of the intact rat. Folli, F., Saad, M.J., Backer, J.M., Kahn, C.R. J. Biol. Chem. (1992) [Pubmed]
  34. Vanadate activates membranous nonreceptor protein tyrosine kinase in rat adipocytes. Elberg, G., He, Z., Li, J., Sekar, N., Shechter, Y. Diabetes (1997) [Pubmed]
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