This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ueki, K.
Right arrow Articles by Kahn, C. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ueki, K.
Right arrow Articles by Kahn, C. R.

 Previous Article

Molecular and Cellular Biology, February 2002, p. 965-977, Vol. 22, No. 3
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.3.965-977.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Molecular Balance between the Regulatory and Catalytic Subunits of Phosphoinositide 3-Kinase Regulates Cell Signaling and Survival

Kohjiro Ueki,1,2 David A. Fruman,3,4 Saskia M. Brachmann,3,4,5 Yu-Hua Tseng,1,2 Lewis C. Cantley,3,4 and C. Ronald Kahn1,2*

Research Division, Joslin Diabetes Center,1 Department of Medicine,2 Department of Cell Biology, Harvard Medical School,3 Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts,4 Institut fuer Biochemie, Freie Universitaet Berlin, Berlin, Germany5

Received 10 May 2001/ Returned for modification 21 June 2001/ Accepted 12 October 2001

Class Ia phosphoinositide (PI) 3-kinase is a central component in growth factor signaling and is comprised of a p110 catalytic subunit and a regulatory subunit, the most common family of which is derived from the p85{alpha} gene (Pik3r1). Optimal signaling through the PI 3-kinase pathway depends on a critical molecular balance between the regulatory and catalytic subunits. In wild-type cells, the p85 subunit is more abundant than p110, leading to competition between the p85 monomer and the p85-p110 dimer and ineffective signaling. Heterozygous disruption of Pik3r1 results in increased Akt activity and decreased apoptosis by insulin-like growth factor 1 (IGF-1) through up-regulated phosphatidylinositol (3,4,5)-triphosphate production. Complete depletion of p85{alpha}, on the other hand, results in significantly increased apoptosis due to reduced PI 3-kinase-dependent signaling. Thus, a reduction in p85{alpha} represents a novel therapeutic target for enhancing IGF-1/insulin signaling, prolongation of cell survival, and protection against apoptosis.

* Corresponding author. Mailing address: Joslin Diabetes Center, One Joslin Pl., Boston, MA 02215. Phone: (617) 732-2635. Fax: (617) 732-2593. E-mail: c.ronald.kahn{at}joslin.harvard.edu.

Molecular and Cellular Biology, February 2002, p. 965-977, Vol. 22, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.3.965-977.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Page, K. C., Malik, R. E., Ripple, J. A., Anday, E. K. (2009). Maternal and postweaning diet interaction alters hypothalamic gene expression and modulates response to a high-fat diet in male offspring. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297: R1049-R1057 [Abstract] [Full Text]  
  • Assmann, A., Ueki, K., Winnay, J. N., Kadowaki, T., Kulkarni, R. N. (2009). Glucose Effects on Beta-Cell Growth and Survival Require Activation of Insulin Receptors and Insulin Receptor Substrate 2. Mol. Cell. Biol. 29: 3219-3228 [Abstract] [Full Text]  
  • Aoki, K., Matsui, J., Kubota, N., Nakajima, H., Iwamoto, K., Takamoto, I., Tsuji, Y., Ohno, A., Mori, S., Tokuyama, K., Murakami, K., Asano, T., Aizawa, S., Tobe, K., Kadowaki, T., Terauchi, Y. (2009). Role of the liver in glucose homeostasis in PI 3-kinase p85{alpha}-deficient mice. Am. J. Physiol. Endocrinol. Metab. 296: E842-E853 [Abstract] [Full Text]  
  • Adochio, R., Leitner, J. W., Hedlund, R., Draznin, B. (2009). Rescuing 3T3-L1 Adipocytes from Insulin Resistance Induced by Stimulation of Akt-Mammalian Target of Rapamycin/p70 S6 Kinase (S6K1) Pathway and Serine Phosphorylation of Insulin Receptor Substrate-1: Effect of Reduced Expression of p85{alpha} Subunit of Phosphatidylinositol 3-Kinase and S6K1 Kinase. Endocrinology 150: 1165-1173 [Abstract] [Full Text]  
  • Kuhnert, F., Mancuso, M. R., Hampton, J., Stankunas, K., Asano, T., Chen, C.-Z., Kuo, C. J. (2008). Attribution of vascular phenotypes of the murine Egfl7 locus to the microRNA miR-126. Development 135: 3989-3993 [Abstract] [Full Text]  
  • Li, Y., Anderson, D. H., Liu, Q., Zhou, Y. (2008). Mechanism of Influenza A Virus NS1 Protein Interaction with the p85{beta}, but Not the p85{alpha}, Subunit of Phosphatidylinositol 3-Kinase (PI3K) and Up-regulation of PI3K Activity. J. Biol. Chem. 283: 23397-23409 [Abstract] [Full Text]  
  • Biswas, S. K., Zhao, Y., Nagalingam, A., Gardner, T. W., Sandirasegarane, L. (2008). PDGF- and Insulin/IGF-1-Specific Distinct Modes of Class IA PI 3-Kinase Activation in Normal Rat Retinas and RGC-5 Retinal Ganglion Cells. IOVS 49: 3687-3698 [Abstract] [Full Text]  
  • Friedman, J. E., Kirwan, J. P., Jing, M., Presley, L., Catalano, P. M. (2008). Increased Skeletal Muscle Tumor Necrosis Factor-{alpha} and Impaired Insulin Signaling Persist in Obese Women With Gestational Diabetes Mellitus 1 Year Postpartum. Diabetes 57: 606-613 [Abstract] [Full Text]  
  • Le Stunff, C., Dechartres, A., Mariot, V., Lotton, C., Trainor, C., Miraglia Del Giudice, E., Meyre, D., Bieche, I., Laurendeau, I., Froguel, P., Zelenika, D., Fallin, D., Lathrop, M., Romeo, P.-H., Bougneres, P. (2008). Association Analysis Indicates That a Variant GATA-Binding Site in the PIK3CB Promoter Is a Cis-Acting Expression Quantitative Trait Locus for This Gene and Attenuates Insulin Resistance in Obese Children. Diabetes 57: 494-502 [Abstract] [Full Text]  
  • Le Stunff, C., Dechartres, A., Miraglia Del Giudice, E., Froguel, P., Bougneres, P. (2008). A Single-Nucleotide Polymorphism in the p110 Gene Promoter Is Associated with Partial Protection from Insulin Resistance in Severely Obese Adolescents. J. Clin. Endocrinol. Metab. 93: 212-215 [Abstract] [Full Text]  
  • Masia, S., Alvarez, S., de Lera, A. R., Barettino, D. (2007). Rapid, Nongenomic Actions of Retinoic Acid on Phosphatidylinositol-3-Kinase Signaling Pathway Mediated by the Retinoic Acid Receptor. Mol. Endocrinol. 21: 2391-2402 [Abstract] [Full Text]  
  • Hirsch, E., Costa, C., Ciraolo, E. (2007). Phosphoinositide 3-kinases as a common platform for multi-hormone signaling. J Endocrinol 194: 243-256 [Abstract] [Full Text]  
  • Kallin, A., Johannessen, L. E., Cani, P. D., Marbehant, C. Y., Essaghir, A., Foufelle, F., Ferre, P., Heldin, C.-H., Delzenne, N. M., Demoulin, J.-B. (2007). SREBP-1 regulates the expression of heme oxygenase 1 and the phosphatidylinositol-3 kinase regulatory subunit p55{gamma}. J. Lipid Res. 48: 1628-1636 [Abstract] [Full Text]  
  • del Rincon, J.-P., Iida, K., Gaylinn, B. D., McCurdy, C. E., Leitner, J. W., Barbour, L. A., Kopchick, J. J., Friedman, J. E., Draznin, B., Thorner, M. O. (2007). Growth Hormone Regulation of p85{alpha} Expression and Phosphoinositide 3-Kinase Activity in Adipose Tissue: Mechanism for Growth Hormone-Mediated Insulin Resistance. Diabetes 56: 1638-1646 [Abstract] [Full Text]  
  • Geering, B., Cutillas, P. R., Nock, G., Gharbi, S. I., Vanhaesebroeck, B. (2007). Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers. Proc. Natl. Acad. Sci. USA 104: 7809-7814 [Abstract] [Full Text]  
  • Wang, X., Hu, J., Price, S. R. (2007). Inhibition of PI3-kinase signaling by glucocorticoids results in increased branched-chain amino acid degradation in renal epithelial cells. Am. J. Physiol. Cell Physiol. 292: C1874-C1879 [Abstract] [Full Text]  
  • Holzman, J. L., Liu, L., Duke, B. J., Kemendy, A. E., Eaton, D. C. (2007). Transactivation of the IGF-1R by aldosterone. Am. J. Physiol. Renal Physiol. 292: F1219-F1228 [Abstract] [Full Text]  
  • Verga Falzacappa, C., Petrucci, E., Patriarca, V., Michienzi, S., Stigliano, A., Brunetti, E., Toscano, V., Misiti, S. (2007). Thyroid hormone receptor TR{beta}1 mediates Akt activation by T3 in pancreatic {beta} cells. J Mol Endocrinol 38: 221-233 [Abstract] [Full Text]  
  • Spender, L. C., Lucchesi, W., Bodelon, G., Bilancio, A., Karstegl, C. E., Asano, T., Dittrich-Breiholz, O., Kracht, M., Vanhaesebroeck, B., Farrell, P. J. (2006). Cell target genes of Epstein-Barr virus transcription factor EBNA-2: induction of the p55{alpha} regulatory subunit of PI3-kinase and its role in survival of EREB2.5 cells.. J. Gen. Virol. 87: 2859-2867 [Abstract] [Full Text]  
  • Taniguchi, C. M., Tran, T. T., Kondo, T., Luo, J., Ueki, K., Cantley, L. C., Kahn, C. R. (2006). Phosphoinositide 3-kinase regulatory subunit p85{alpha} suppresses insulin action via positive regulation of PTEN. Proc. Natl. Acad. Sci. USA 103: 12093-12097 [Abstract] [Full Text]  
  • Draznin, B. (2006). Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85{alpha}: The Two Sides of a Coin.. Diabetes 55: 2392-2397 [Abstract] [Full Text]  
  • Bailey, J. L., Zheng, B., Hu, Z., Price, S. R., Mitch, W. E. (2006). Chronic Kidney Disease Causes Defects in Signaling through the Insulin Receptor Substrate/Phosphatidylinositol 3-Kinase/Akt Pathway: Implications for Muscle Atrophy. J. Am. Soc. Nephrol. 17: 1388-1394 [Abstract] [Full Text]  
  • Peloponese, J.-M. Jr., Jeang, K.-T. (2006). Role for Akt/Protein Kinase B and Activator Protein-1 in Cellular Proliferation Induced by the Human T-cell Leukemia Virus Type 1 Tax Oncoprotein. J. Biol. Chem. 281: 8927-8938 [Abstract] [Full Text]  
  • Weigert, C., Hennige, A. M., Lehmann, R., Brodbeck, K., Baumgartner, F., Schauble, M., Haring, H. U., Schleicher, E. D. (2006). Direct Cross-talk of Interleukin-6 and Insulin Signal Transduction via Insulin Receptor Substrate-1 in Skeletal Muscle Cells. J. Biol. Chem. 281: 7060-7067 [Abstract] [Full Text]  
  • Kang, S., Denley, A., Vanhaesebroeck, B., Vogt, P. K. (2006). Oncogenic transformation induced by the p110beta, -{gamma}, and -{delta} isoforms of class I phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. USA 103: 1289-1294 [Abstract] [Full Text]  
  • Barbour, L. A., Mizanoor Rahman, S., Gurevich, I., Leitner, J. W., Fischer, S. J., Roper, M. D., Knotts, T. A., Vo, Y., McCurdy, C. E., Yakar, S., LeRoith, D., Kahn, C. R., Cantley, L. C., Friedman, J. E., Draznin, B. (2005). Increased P85{alpha} Is a Potent Negative Regulator of Skeletal Muscle Insulin Signaling and Induces in Vivo Insulin Resistance Associated with Growth Hormone Excess. J. Biol. Chem. 280: 37489-37494 [Abstract] [Full Text]  
  • Basile, J. R., Afkhami, T., Gutkind, J. S. (2005). Semaphorin 4D/Plexin-B1 Induces Endothelial Cell Migration through the Activation of PYK2, Src, and the Phosphatidylinositol 3-Kinase-Akt Pathway. Mol. Cell. Biol. 25: 6889-6898 [Abstract] [Full Text]  
  • Luo, J., Field, S. J., Lee, J. Y., Engelman, J. A., Cantley, L. C. (2005). The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex. JCB 170: 455-464 [Abstract] [Full Text]  
  • Bandyopadhyay, G. K., Yu, J. G., Ofrecio, J., Olefsky, J. M. (2005). Increased p85/55/50 Expression and Decreased Phosphotidylinositol 3-Kinase Activity in Insulin-Resistant Human Skeletal Muscle. Diabetes 54: 2351-2359 [Abstract] [Full Text]  
  • Hennige, A. M., Ozcan, U., Okada, T., Jhala, U. S., Schubert, M., White, M. F., Kulkarni, R. N. (2005). Alterations in growth and apoptosis of insulin receptor substrate-1-deficient {beta}-cells. Am. J. Physiol. Endocrinol. Metab. 289: E337-E346 [Abstract] [Full Text]  
  • Shekar, S. C., Wu, H., Fu, Z., Yip, S.-C., Nagajyothi, , Cahill, S. M., Girvin, M. E., Backer, J. M. (2005). Mechanism of Constitutive Phosphoinositide 3-Kinase Activation by Oncogenic Mutants of the p85 Regulatory Subunit. J. Biol. Chem. 280: 27850-27855 [Abstract] [Full Text]  
  • Luo, J., Sobkiw, C. L., Logsdon, N. M., Watt, J. M., Signoretti, S., O'Connell, F., Shin, E., Shim, Y., Pao, L., Neel, B. G., DePinho, R. A., Loda, M., Cantley, L. C. (2005). Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/- mice by the p85 regulatory subunits of phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. USA 102: 10238-10243 [Abstract] [Full Text]  
  • Fukui, K., Wada, T., Kagawa, S., Nagira, K., Ikubo, M., Ishihara, H., Kobayashi, M., Sasaoka, T. (2005). Impact of the Liver-Specific Expression of SHIP2 (SH2-Containing Inositol 5'-Phosphatase 2) on Insulin Signaling and Glucose Metabolism in Mice. Diabetes 54: 1958-1967 [Abstract] [Full Text]  
  • Coffey, J. C., Wang, J. H., Smith, M. J. F., Laing, A., Bouchier-Hayes, D., Cotter, T. G., Redmond, H. P. (2005). Phosphoinositide 3-Kinase Accelerates Postoperative Tumor Growth by Inhibiting Apoptosis and Enhancing Resistance to Chemotherapy-induced Apoptosis: NOVEL ROLE FOR AN OLD ENEMY. J. Biol. Chem. 280: 20968-20977 [Abstract] [Full Text]  
  • McCurdy, C. E., Davidson, R. T., Cartee, G. D. (2005). Calorie restriction increases the ratio of phosphatidylinositol 3-kinase catalytic to regulatory subunits in rat skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 288: E996-E1001 [Abstract] [Full Text]  
  • Brachmann, S. M., Ueki, K., Engelman, J. A., Kahn, R. C., Cantley, L. C. (2005). Phosphoinositide 3-Kinase Catalytic Subunit Deletion and Regulatory Subunit Deletion Have Opposite Effects on Insulin Sensitivity in Mice. Mol. Cell. Biol. 25: 1596-1607 [Abstract] [Full Text]  
  • Chamberlain, M. D., Berry, T. R., Pastor, M. C., Anderson, D. H. (2004). The p85{alpha} Subunit of Phosphatidylinositol 3'-Kinase Binds to and Stimulates the GTPase Activity of Rab Proteins. J. Biol. Chem. 279: 48607-48614 [Abstract] [Full Text]  
  • Franch, H. A., Raissi, S., Wang, X., Zheng, B., Bailey, J. L., Price, S. R. (2004). Acidosis impairs insulin receptor substrate-1-associated phosphoinositide 3-kinase signaling in muscle cells: consequences on proteolysis. Am. J. Physiol. Renal Physiol. 287: F700-F706 [Abstract] [Full Text]  
  • Kirwan, J. P., Varastehpour, A., Jing, M., Presley, L., Shao, J., Friedman, J. E., Catalano, P. M. (2004). Reversal of Insulin Resistance Postpartum Is Linked to Enhanced Skeletal Muscle Insulin Signaling. J. Clin. Endocrinol. Metab. 89: 4678-4684 [Abstract] [Full Text]  
  • Terauchi, Y., Matsui, J., Kamon, J., Yamauchi, T., Kubota, N., Komeda, K., Aizawa, S., Akanuma, Y., Tomita, M., Kadowaki, T. (2004). Increased Serum Leptin Protects From Adiposity Despite the Increased Glucose Uptake in White Adipose Tissue in Mice Lacking p85{alpha} Phosphoinositide 3-Kinase. Diabetes 53: 2261-2270 [Abstract] [Full Text]  
  • Li, L., Gronning, L. M., Anderson, P. O., Li, S., Edvardsen, K., Johnston, J., Kioussis, D., Shepherd, P. R., Wang, P. (2004). Insulin Induces SOCS-6 Expression and Its Binding to the p85 Monomer of Phosphoinositide 3-Kinase, Resulting in Improvement in Glucose Metabolism. J. Biol. Chem. 279: 34107-34114 [Abstract] [Full Text]  
  • Lee, J. S., Hmama, Z., Mui, A., Reiner, N. E. (2004). Stable Gene Silencing in Human Monocytic Cell Lines Using Lentiviral-delivered Small Interference RNA: SILENCING OF THE p110{alpha} ISOFORM OF PHOSPHOINOSITIDE 3-KINASE REVEALS DIFFERENTIAL REGULATION OF ADHERENCE INDUCED BY 1{alpha},25-DIHYDROXYCHOLECALCIFEROL AND BACTERIAL LIPOPOLYSACCHARIDE. J. Biol. Chem. 279: 9379-9388 [Abstract] [Full Text]  
  • Foukas, L. C., Beeton, C. A., Jensen, J., Phillips, W. A., Shepherd, P. R. (2004). Regulation of Phosphoinositide 3-Kinase by Its Intrinsic Serine Kinase Activity In Vivo. Mol. Cell. Biol. 24: 966-975 [Abstract] [Full Text]  
  • Chen, D., Mauvais-Jarvis, F., Bluher, M., Fisher, S. J., Jozsi, A., Goodyear, L. J., Ueki, K., Kahn, C. R. (2004). p50{alpha}/p55{alpha} Phosphoinositide 3-Kinase Knockout Mice Exhibit Enhanced Insulin Sensitivity. Mol. Cell. Biol. 24: 320-329 [Abstract] [Full Text]  
  • Li, Y., Higashi, Y., Itabe, H., Song, Y.-H., Du, J., Delafontaine, P. (2003). Insulin-Like Growth Factor-1 Receptor Activation Inhibits Oxidized LDL-Induced Cytochrome C Release and Apoptosis via the Phosphatidylinositol 3 Kinase/Akt Signaling Pathway. Arterioscler. Thromb. Vasc. Bio. 23: 2178-2184 [Abstract] [Full Text]  
  • Ueki, K., Fruman, D. A., Yballe, C. M., Fasshauer, M., Klein, J., Asano, T., Cantley, L. C., Kahn, C. R. (2003). Positive and Negative Roles of p85{alpha} and p85{beta} Regulatory Subunits of Phosphoinositide 3-Kinase in Insulin Signaling. J. Biol. Chem. 278: 48453-48466 [Abstract] [Full Text]  
  • Sun, M., Yang, L., Feldman, R. I., Sun, X.-m., Bhalla, K. N., Jove, R., Nicosia, S. V., Cheng, J. Q. (2003). Activation of Phosphatidylinositol 3-Kinase/Akt Pathway by Androgen through Interaction of p85{alpha}, Androgen Receptor, and Src. J. Biol. Chem. 278: 42992-43000 [Abstract] [Full Text]  
  • Chodniewicz, D., Zhelev, D. V. (2003). Novel pathways of F-actin polymerization in the human neutrophil. Blood 102: 2251-2258 [Abstract] [Full Text]  
  • Huddleston, H., Tan, B., Yang, F.-C., White, H., Wenning, M. J., Orazi, A., Yoder, M. C., Kapur, R., Ingram, D. A. (2003). Functional p85{alpha} gene is required for normal murine fetal erythropoiesis. Blood 102: 142-145 [Abstract] [Full Text]  
  • Liu, K.-p., Russo, A. F., Hsiung, S.-c., Adlersberg, M., Franke, T. F., Gershon, M. D., Tamir, H. (2003). Calcium Receptor-Induced Serotonin Secretion by Parafollicular Cells: Role of Phosphatidylinositol 3-Kinase-Dependent Signal Transduction Pathways. J. Neurosci. 23: 2049-2057 [Abstract] [Full Text]  
  • Hallmann, D., Trumper, K., Trusheim, H., Ueki, K., Kahn, C. R., Cantley, L. C., Fruman, D. A., Horsch, D. (2003). Altered Signaling and Cell Cycle Regulation in Embryonal Stem Cells with a Disruption of the Gene for Phosphoinositide 3-Kinase Regulatory Subunit p85alpha. J. Biol. Chem. 278: 5099-5108 [Abstract] [Full Text]  
  • Brock, C., Schaefer, M., Reusch, H. P., Czupalla, C., Michalke, M., Spicher, K., Schultz, G., Nurnberg, B. (2003). Roles of G{beta}{gamma} in membrane recruitment and activation of p110{gamma}/p101 phosphoinositide 3-kinase {gamma}. JCB 160: 89-99 [Abstract] [Full Text]  
  • Yellaturu, C. R., Bhanoori, M., Neeli, I., Rao, G. N. (2002). N-Ethylmaleimide Inhibits Platelet-derived Growth Factor BB-stimulated Akt Phosphorylation via Activation of Protein Phosphatase 2A. J. Biol. Chem. 277: 40148-40155 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»