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Pik3r1  -  phosphatidylinositol 3-kinase, regulatory...

Mus musculus

 
 
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Disease relevance of Pik3r1

  • After 3 months on a high-fat diet, Pik3r1(-/-) mice still had increased insulin sensitivity and better glucose tolerance than wild-type mice, but showed markedly greater increases in body weight and WAT mass than wild-type mice [1].
  • Consequently, leptin secretion was unable to sufficiently compensate for the severe leptin resistance caused by the high-fat diet, thereby failing to prevent obesity in Pik3r1(-/-) mice [1].
  • In addition, inhibition of in vitro proliferation and in vivo liver metastasis by p85alpha or p110alpha siRNA treatment was analyzed [2].
  • HT29 and KM20 human colon cancer cells were treated with siRNA directed to p85alpha or p110alpha, and cell viability and apoptosis assessed [2].
  • As with the p85alpha(-/-) mice, the p85beta(-/-) mice showed hypoinsulinemia, hypoglycemia, and improved insulin sensitivity [3].
 

High impact information on Pik3r1

 

Chemical compound and disease context of Pik3r1

 

Biological context of Pik3r1

 

Anatomical context of Pik3r1

 

Associations of Pik3r1 with chemical compounds

 

Physical interactions of Pik3r1

 

Enzymatic interactions of Pik3r1

  • In contrast, in the transformed mast cell line P815, Kit is constitutively phosphorylated and binds to PI3K in the absence of ligand [27].
  • IL-4 treatment of FDCP-2 cells caused a dramatically strong association of phosphatidylinositol 3-kinase (PI 3-kinase) both with the 170 kDa tyrosine phosphorylated substrate and with the IL-4 receptor itself [28].
  • This appears to be due, in large part, to the specific association of PI 3-kinase with the tyrosine-phosphorylated EpR, either directly or through a 93- or 70-Kd tyrosine-phosphorylated intermediate [29].
  • When p110alpha and p110beta were overexpressed in 3T3-L1 adipocytes, exposing cells to insulin induced each of the subunits to form complexes with p85alpha and tyrosine-phosphorylated IRS-1 with similar efficiency [30].
  • Bacterially expressed p85 alpha SH2 domains complexed in vitro with the tyrosine phosphorylated CSF-1R KI [31].
 

Regulatory relationships of Pik3r1

 

Other interactions of Pik3r1

  • Thus, despite the decrease in p85alpha, PI 3-kinase activation is normal, insulin-stimulated Akt activity is increased, and glucose tolerance and insulin sensitivity are improved [12].
  • Insulin signaling proteins, insulin receptor substrate 2 and phosphatidylinositol 3 (PI3)-kinase regulatory subunit p50alpha, were increased and PI3-kinase p85alpha expression was decreased in liver and fat [34].
  • Effects of Lyn, PTEN, or p85alpha haploinsufficiency were observed [35].
  • Using genetic intercrosses between Nf1 +/- and class I (A)-PI-3K-deficient mice, we demonstrate that hyperactivation of the p21(ras)-class I(A) PI-3K pathway is the mechanism for this phenotype [36].
  • 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 [37].
 

Analytical, diagnostic and therapeutic context of Pik3r1

  • For example, microinjection of antibodies, peptides, or recombinant proteins which block the interaction of the SH2 domains of the PI 3-k p85alpha subunit with tyrosine phosphorylated intracellular targets blocks insulin mediated DNA synthesis [38].
  • By contrast, dexamethasone induced a 69% increase in the level of PI 3-kinase as determined by immunoblotting [39].
  • ELISA revealed that the two CD19 cytoplasmic tyrosine residues contained within the Y-X-X-M sequences (Y484 and Y515) bound preferentially to the PI-3 kinase SH2-domain fusion proteins [40].
  • Northern blot analysis of mouse tissues reveals differential expression of full-length and alternatively spliced p85 alpha, with the splice variant most abundant in the liver [41].
  • HPLC analysis of the GLUT4 vesicle-associated PI 3-kinase activity showed insulin-mediated increases in PI 3-P, PI 3,4-P2, and PI 3,4,5-P3 when PI, PI 4-P, and PI 4,5-P2 were used as substrates [42].

References

  1. Increased serum leptin protects from adiposity despite the increased glucose uptake in white adipose tissue in mice lacking p85alpha phosphoinositide 3-kinase. Terauchi, Y., Matsui, J., Kamon, J., Yamauchi, T., Kubota, N., Komeda, K., Aizawa, S., Akanuma, Y., Tomita, M., Kadowaki, T. Diabetes (2004) [Pubmed]
  2. Targeted molecular therapy of the PI3K pathway: therapeutic significance of PI3K subunit targeting in colorectal carcinoma. Rychahou, P.G., Jackson, L.N., Silva, S.R., Rajaraman, S., Evers, B.M. Ann. Surg. (2006) [Pubmed]
  3. Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. Ueki, K., Yballe, C.M., Brachmann, S.M., Vicent, D., Watt, J.M., Kahn, C.R., Cantley, L.C. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  4. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Knight, Z.A., Gonzalez, B., Feldman, M.E., Zunder, E.R., Goldenberg, D.D., Williams, O., Loewith, R., Stokoe, D., Balla, A., Toth, B., Balla, T., Weiss, W.A., Williams, R.L., Shokat, K.M. Cell (2006) [Pubmed]
  5. Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha. Fruman, D.A., Mauvais-Jarvis, F., Pollard, D.A., Yballe, C.M., Brazil, D., Bronson, R.T., Kahn, C.R., Cantley, L.C. Nat. Genet. (2000) [Pubmed]
  6. Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Terauchi, Y., Tsuji, Y., Satoh, S., Minoura, H., Murakami, K., Okuno, A., Inukai, K., Asano, T., Kaburagi, Y., Ueki, K., Nakajima, H., Hanafusa, T., Matsuzawa, Y., Sekihara, H., Yin, Y., Barrett, J.C., Oda, H., Ishikawa, T., Akanuma, Y., Komuro, I., Suzuki, M., Yamamura, K., Kodama, T., Suzuki, H., Yamamura, K., Kodama, T., Suzuki, H., Koyasu, S., Aizawa, S., Tobe, K., Fukui, Y., Yazaki, Y., Kadowaki, T. Nat. Genet. (1999) [Pubmed]
  7. Insulin receptor substrate-2-dependent interleukin-4 signaling in macrophages is impaired in two models of type 2 diabetes mellitus. Hartman, M.E., O'Connor, J.C., Godbout, J.P., Minor, K.D., Mazzocco, V.R., Freund, G.G. J. Biol. Chem. (2004) [Pubmed]
  8. Phosphatidylinositol 3-kinase binding to polyoma virus middle tumor antigen mediates elevation of glucose transport by increasing translocation of the GLUT1 transporter. Young, A.T., Dahl, J., Hausdorff, S.F., Bauer, P.H., Birnbaum, M.J., Benjamin, T.L. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  9. Phosphoinositide 3-kinase in nitric oxide synthesis in macrophage: critical dimerization of inducible nitric-oxide synthase. Sakai, K., Suzuki, H., Oda, H., Akaike, T., Azuma, Y., Murakami, T., Sugi, K., Ito, T., Ichinose, H., Koyasu, S., Shirai, M. J. Biol. Chem. (2006) [Pubmed]
  10. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) reduces vascular endothelial growth factor expression in allergen-induced airway inflammation. Lee, K.S., Kim, S.R., Park, S.J., Lee, H.K., Park, H.S., Min, K.H., Jin, S.M., Lee, Y.C. Mol. Pharmacol. (2006) [Pubmed]
  11. Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. Kharas, M.G., Janes, M.R., Scarfone, V.M., Lilly, M.B., Knight, Z.A., Shokat, K.M., Fruman, D.A. J. Clin. Invest. (2008) [Pubmed]
  12. Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. Mauvais-Jarvis, F., Ueki, K., Fruman, D.A., Hirshman, M.F., Sakamoto, K., Goodyear, L.J., Iannacone, M., Accili, D., Cantley, L.C., Kahn, C.R. J. Clin. Invest. (2002) [Pubmed]
  13. Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Ueki, K., Fruman, D.A., Brachmann, S.M., Tseng, Y.H., Cantley, L.C., Kahn, C.R. Mol. Cell. Biol. (2002) [Pubmed]
  14. Aging is associated with decreased pancreatic acinar cell regeneration and phosphatidylinositol 3-kinase/Akt activation. Watanabe, H., Saito, H., Rychahou, P.G., Uchida, T., Evers, B.M. Gastroenterology (2005) [Pubmed]
  15. The inability of phosphatidylinositol 3-kinase activation to stimulate GLUT4 translocation indicates additional signaling pathways are required for insulin-stimulated glucose uptake. Isakoff, S.J., Taha, C., Rose, E., Marcusohn, J., Klip, A., Skolnik, E.Y. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  16. Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha. Fruman, D.A., Snapper, S.B., Yballe, C.M., Davidson, L., Yu, J.Y., Alt, F.W., Cantley, L.C. Science (1999) [Pubmed]
  17. Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells. Yang, F.C., Ingram, D.A., Chen, S., Hingtgen, C.M., Ratner, N., Monk, K.R., Clegg, T., White, H., Mead, L., Wenning, M.J., Williams, D.A., Kapur, R., Atkinson, S.J., Clapp, D.W. J. Clin. Invest. (2003) [Pubmed]
  18. P110delta, a novel phosphoinositide 3-kinase in leukocytes. Vanhaesebroeck, B., Welham, M.J., Kotani, K., Stein, R., Warne, P.H., Zvelebil, M.J., Higashi, K., Volinia, S., Downward, J., Waterfield, M.D. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  19. p50alpha/p55alpha phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity. Chen, D., Mauvais-Jarvis, F., Bluher, M., Fisher, S.J., Jozsi, A., Goodyear, L.J., Ueki, K., Kahn, C.R. Mol. Cell. Biol. (2004) [Pubmed]
  20. Functional phenotype of phosphoinositide 3-kinase p85alpha-null platelets characterized by an impaired response to GP VI stimulation. Watanabe, N., Nakajima, H., Suzuki, H., Oda, A., Matsubara, Y., Moroi, M., Terauchi, Y., Kadowaki, T., Suzuki, H., Koyasu, S., Ikeda, Y., Handa, M. Blood (2003) [Pubmed]
  21. Impaired kit- but not FcepsilonRI-initiated mast cell activation in the absence of phosphoinositide 3-kinase p85alpha gene products. Lu-Kuo, J.M., Fruman, D.A., Joyal, D.M., Cantley, L.C., Katz, H.R. J. Biol. Chem. (2000) [Pubmed]
  22. Multiple cytokines activate phosphatidylinositol 3-kinase in hemopoietic cells. Association of the enzyme with various tyrosine-phosphorylated proteins. Gold, M.R., Duronio, V., Saxena, S.P., Schrader, J.W., Aebersold, R. J. Biol. Chem. (1994) [Pubmed]
  23. Effects of dietary calorie restriction or exercise on the PI3K and Ras signaling pathways in the skin of mice. Xie, L., Jiang, Y., Ouyang, P., Chen, J., Doan, H., Herndon, B., Sylvester, J.E., Zhang, K., Molteni, A., Reichle, M., Zhang, R., Haub, M.D., Baybutt, R.C., Wang, W. J. Biol. Chem. (2007) [Pubmed]
  24. Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition. Abell, K., Bilancio, A., Clarkson, R.W., Tiffen, P.G., Altaparmakov, A.I., Burdon, T.G., Asano, T., Vanhaesebroeck, B., Watson, C.J. Nat. Cell Biol. (2005) [Pubmed]
  25. Direct metabolic regulation of beta-catenin activity by the p85alpha regulatory subunit of phosphoinositide 3-OH kinase. Espada, J., Peinado, H., Esteller, M., Cano, A. Exp. Cell Res. (2005) [Pubmed]
  26. Role of TC21/R-Ras2 in enhanced migration of neurofibromin-deficient Schwann cells. Huang, Y., Rangwala, F., Fulkerson, P.C., Ling, B., Reed, E., Cox, A.D., Kamholz, J., Ratner, N. Oncogene (2004) [Pubmed]
  27. The Steel/W transduction pathway: kit autophosphorylation and its association with a unique subset of cytoplasmic signaling proteins is induced by the Steel factor. Rottapel, R., Reedijk, M., Williams, D.E., Lyman, S.D., Anderson, D.M., Pawson, T., Bernstein, A. Mol. Cell. Biol. (1991) [Pubmed]
  28. IL-4 activates a distinct signal transduction cascade from IL-3 in factor-dependent myeloid cells. Wang, L.M., Keegan, A.D., Paul, W.E., Heidaran, M.A., Gutkind, J.S., Pierce, J.H. EMBO J. (1992) [Pubmed]
  29. Phosphatidylinositol 3-kinase associates, via its Src homology 2 domains, with the activated erythropoietin receptor. Damen, J.E., Mui, A.L., Puil, L., Pawson, T., Krystal, G. Blood (1993) [Pubmed]
  30. p110beta is up-regulated during differentiation of 3T3-L1 cells and contributes to the highly insulin-responsive glucose transport activity. Asano, T., Kanda, A., Katagiri, H., Nawano, M., Ogihara, T., Inukai, K., Anai, M., Fukushima, Y., Yazaki, Y., Kikuchi, M., Hooshmand-Rad, R., Heldin, C.H., Oka, Y., Funaki, M. J. Biol. Chem. (2000) [Pubmed]
  31. Tyr721 regulates specific binding of the CSF-1 receptor kinase insert to PI 3'-kinase SH2 domains: a model for SH2-mediated receptor-target interactions. Reedijk, M., Liu, X., van der Geer, P., Letwin, K., Waterfield, M.D., Hunter, T., Pawson, T. EMBO J. (1992) [Pubmed]
  32. Phosphatidylinositol 3-kinase-dependent mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 and NF-kappa B signaling pathways are required for B cell antigen receptor-mediated cyclin D2 induction in mature B cells. Piatelli, M.J., Wardle, C., Blois, J., Doughty, C., Schram, B.R., Rothstein, T.L., Chiles, T.C. J. Immunol. (2004) [Pubmed]
  33. Reduction of PTP1B induces differential expression of PI3-kinase (p85alpha) isoforms. Rondinone, C.M., Clampit, J., Gum, R.J., Zinker, B.A., Jirousek, M.R., Trevillyan, J.M. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  34. PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Zinker, B.A., Rondinone, C.M., Trevillyan, J.M., Gum, R.J., Clampit, J.E., Waring, J.F., Xie, N., Wilcox, D., Jacobson, P., Frost, L., Kroeger, P.E., Reilly, R.M., Koterski, S., Opgenorth, T.J., Ulrich, R.G., Crosby, S., Butler, M., Murray, S.F., McKay, R.A., Bhanot, S., Monia, B.P., Jirousek, M.R. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  35. A sensitized genetic system for the analysis of murine B lymphocyte signal transduction pathways dependent on Bruton's tyrosine kinase. Satterthwaite, A.B., Willis, F., Kanchanastit, P., Fruman, D., Cantley, L.C., Helgason, C.D., Humphries, R.K., Lowell, C.A., Simon, M., Leitges, M., Tarakhovsky, A., Tedder, T.F., Lesche, R., Wu, H., Witte, O.N. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  36. Loss of the nf1 tumor suppressor gene decreases fas antigen expression in myeloid cells. Hiatt, K., Ingram, D.A., Huddleston, H., Spandau, D.F., Kapur, R., Clapp, D.W. Am. J. Pathol. (2004) [Pubmed]
  37. Galpha q inhibits cardiac L-type Ca2+ channels through phosphatidylinositol 3-kinase. Lu, Z., Jiang, Y.P., Ballou, L.M., Cohen, I.S., Lin, R.Z. J. Biol. Chem. (2005) [Pubmed]
  38. Prolonged vs transient roles for early cell cycle signaling components. Rose, D.W., Xiao, S., Pillay, T.S., Kolch, W., Olefsky, J.M. Oncogene (1998) [Pubmed]
  39. Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. Effects of differentiation, insulin, and dexamethasone. Saad, M.J., Folli, F., Araki, E., Hashimoto, N., Csermely, P., Kahn, C.R. Mol. Endocrinol. (1994) [Pubmed]
  40. Specific binding of Fyn and phosphatidylinositol 3-kinase to the B cell surface glycoprotein CD19 through their src homology 2 domains. Chalupny, N.J., Aruffo, A., Esselstyn, J.M., Chan, P.Y., Bajorath, J., Blake, J., Gilliland, L.K., Ledbetter, J.A., Tepper, M.A. Eur. J. Immunol. (1995) [Pubmed]
  41. Structural organization and alternative splicing of the murine phosphoinositide 3-kinase p85 alpha gene. Fruman, D.A., Cantley, L.C., Carpenter, C.L. Genomics (1996) [Pubmed]
  42. Insulin-mediated targeting of phosphatidylinositol 3-kinase to GLUT4-containing vesicles. Heller-Harrison, R.A., Morin, M., Guilherme, A., Czech, M.P. J. Biol. Chem. (1996) [Pubmed]
 
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