Advertisement

Phosphoinositides in Insulin Action and Diabetes

  • Dave Bridges
  • Alan R. Saltiel
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 362)

Abstract

Phosphoinositides play an essential role in insulin signaling, serving as a localization signal for a variety of proteins that participate in the regulation of cellular growth and metabolism. This chapter will examine the regulation and localization of phosphoinositide species, and will explore the roles of these lipids in insulin action. We will also discuss the changes in phosphoinositide metabolism that occur in various pathophysiological states such as insulin resistance and diabetes.

Keywords

GLUT4 Translocation Normal Chow Diet White Adipose Tissue Depot Lysosomal Localization GLUT4 Trafficking 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors would like to thank Drs. Dara Leto, David Buchner, Binbin Lu, Irit Hochberg and Diane Fingar (University of Michigan), and Dr. Alan Cheng (University of Louisville) for critical discussions and suggestions during the writing of this chapter.

References

  1. Abel ED, Peroni O, Kim JK et al (2001) Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409:729–733. doi: 10.1038/35055575 PubMedGoogle Scholar
  2. Alessi DR, Andjelkovic M, Caudwell B et al (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15:6541–6551PubMedGoogle Scholar
  3. Alessi DR, James SR, Downes CP et al (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7:261–269. doi: S0960-9822(06)00122-9 [pii]PubMedGoogle Scholar
  4. Auger KR, Serunian LA, Soltoff SP et al (1989) PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell 57:167–175PubMedGoogle Scholar
  5. Backer JM (2008) The regulation and function of class III PI3Ks: novel roles for Vps34. Biochem J 410:1–17. doi: 10.1042/BJ20071427 PubMedGoogle Scholar
  6. Balla A, Balla T (2006) Phosphatidylinositol 4-kinases: old enzymes with emerging functions. Trends Cell Biol 16:351–361. doi: 10.1016/j.tcb.2006.05.003 PubMedGoogle Scholar
  7. Barber DF, Alvarado-Kristensson M, González-García A et al (2006) PTEN regulation, a novel function for the p85 subunit of phosphoinositide 3-kinase. Science’s STKE Signal Transduct Knowl Environ 2006:pe49. doi: 10.1126/stke.3622006pe49
  8. Begley M, Dixon J (2005) The structure and regulation of myotubularin phosphatases. Curr Opin Struct Biol 15:614–620PubMedGoogle Scholar
  9. Berwick DC, Dell G, Welsh G et al (2004) Protein kinase B phosphorylation of PIKfyve regulates the trafficking of GLUT4 vesicles. J Cell Sci 117:5985–5993PubMedGoogle Scholar
  10. Bi L, Okabe I, Bernard DJ et al (1999) Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110 subunit of phosphoinositide 3-kinase. J Biol Chem 274:10963–10968PubMedGoogle Scholar
  11. Bi L, Okabe I, Bernard DJ, Nussbaum RL (2002) Early embryonic lethality in mice deficient in the p110 catalytic subunit of PI 3-kinase. New York 172:169–172. doi: 10.1007/s00335-001-2123-x Google Scholar
  12. Binda M, Péli-Gulli M-P, Bonfils G et al (2009) The Vam6 GEF controls TORC1 by activating the EGO complex. Mol Cell 35:563–573. doi: 10.1016/j.molcel.2009.06.033 PubMedGoogle Scholar
  13. Bohdanowicz M, Balkin DM, De Camilli P, Grinstein S (2011) Recruitment of OCRL and Inpp 5B to phagosomes by Rab5 and APPL1 depletes phosphoinositides and attenuates Akt signaling. Mol Biol Cell 23:176–187 doi: 10.1091/mbc.E11-06-0489 PubMedGoogle Scholar
  14. Bonangelino C, Catlett NL, Weisman LS (1997) Vac7p, a novel vacuolar protein, is required for normal vacuole inheritance and morphology. Mol Cell Biol 17:6847–6858PubMedGoogle Scholar
  15. Boronenkov IV, Anderson RA (1995) The sequence of phosphatidylinositol-4-phosphate 5-kinase defines a novel family of lipid kinases. J Biol Chem 270:2881–2884PubMedGoogle Scholar
  16. Botelho RJ, Efe JA, Teis D, Emr SD (2008) Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4 phosphoinositide phosphatase. Mol Biol Cell 19:4273–4286PubMedGoogle Scholar
  17. Brachmann SM, Ueki K, Engelman JA et al (2005) Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. Society 25:1596–1607. doi: 10.1128/MCB.25.5.1596 Google Scholar
  18. Brand RM, Hamel FG (1999) Transdermally delivered peroxovanadium can lower blood glucose levels in diabetic rats. Int J Pharm 183:117–123PubMedGoogle Scholar
  19. Bultsma Y, Keune W-J, Divecha N (2010) PIP4Kbeta interacts with and modulates nuclear localization of the high-activity PtdIns5P-4-kinase isoform PIP4Kalpha. Biochem J 430:223–235. doi: 10.1042/BJ20100341 PubMedGoogle Scholar
  20. Burgering BM, Coffer PJ (1995) Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376:599–602. doi: 10.1038/376599a0 PubMedGoogle Scholar
  21. Butler M, McKay RA, Popoff IJ et al (2002) Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice. Diabetes 51:1028–1034PubMedGoogle Scholar
  22. Byfield MP, Murray JT, Backer JM (2005) hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem 280:33076–33082. doi: 10.1074/jbc.M507201200 M507201200 [pii]PubMedGoogle Scholar
  23. Chagpar RB, Links PH, Pastor MC et al (2010) Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A 107:5471–5476. doi: 10.1073/pnas.0908899107 PubMedGoogle Scholar
  24. Chamberlain M, Berry T, Pastor M, Anderson DH (2004) The p85{alpha} subunit of phosphatidylinositol 3′-kinase binds to and stimulates the GTPase activity of Rab proteins. J Biol Chem 279:48607–48614PubMedGoogle Scholar
  25. Chattopadhyay M, Selinger ES, Ballou LM, Lin RZ (2011) Ablation of PI3K p110-a prevents high-fat diet-induced liver steatosis. Liver. doi: 10.2337/db10-0869 Google Scholar
  26. Chaussade C, Pirola L, Bonnafous S et al (2003) Expression of myotubularin by an adenoviral vector demonstrates its function as a phosphatidylinositol 3-phosphate [PtdIns(3)P] phosphatase in muscle cell lines: involvement of PtdIns(3)P in insulin-stimulated glucose transport. Mol Endocrinol (Baltimore, Md) 17:2448–2460. doi: 10.1210/me.2003-0261 Google Scholar
  27. Chen XW, Leto D, Chiang SH et al (2007) Activation of RalA is required for insulin-stimulated Glut4 trafficking to the plasma membrane via the exocyst and the motor protein Myo1c. Dev Cell 13:391–404. doi: 10.1016/j.devcel.2007.07.007 S1534-5807(07)00268-7 [pii]PubMedGoogle Scholar
  28. Chen X-W, Leto D, Xiong T et al (2011) A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action. Mol Biol Cell 22:141–152. doi: 10.1091/mbc.E10-08-0665 PubMedGoogle Scholar
  29. Chow C, Zhang Y, Dowling JJ et al (2007) Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 448:68–72PubMedGoogle Scholar
  30. Christoforidis S, Miaczynska M, Ashman K et al (1999) Phosphatidylinositol-3-OH kinases are Rab5 effectors. Nat Cell Biol 1:249–252PubMedGoogle Scholar
  31. Ciraolo E, Iezzi M, Marone R et al (2008) Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development. Science Signal 1:ra3. doi: 10.1126/scisignal.1161577
  32. Clark AS, Fagan JM, Mitch WE (1985) Selectivity of the insulin-like actions of vanadate on glucose and protein metabolism in skeletal muscle. Biochem J 232:273–276PubMedGoogle Scholar
  33. Clarke JF, Young PW, Yonezawa K et al (1994) Inhibition of the translocation of GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinositol 3-kinase inhibitor, wortmannin. Biochem J 300(Pt 3):631–635Google Scholar
  34. Clément S, Krause U, Desmedt F et al (2001) The lipid phosphatase SHIP2 controls insulin sensitivity. Nature 409:92–97. doi: 10.1038/35051094 PubMedGoogle Scholar
  35. Cleves AE, Novick PJ, Bankaitis VA (1989) Mutations in the SAC1 gene suppress defects in yeast Golgi and yeast actin function. J Cell Biol 109:2939–2950. doi: 10.1016/0168-9525(90)90063-C PubMedGoogle Scholar
  36. Currie RA, Walker KS, Gray A et al (1999) Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. Biochem J 337(Pt 3):575–583Google Scholar
  37. Dan HC, Sun M, Yang L et al (2002) Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 277:35364–35370. doi: 10.1074/jbc.M205838200 PubMedGoogle Scholar
  38. Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–657. doi: 10.1038/nature05185 PubMedGoogle Scholar
  39. Divecha N, Truong O, Hsuan JJ et al (1995) The cloning and sequence of the C isoform of PtdIns4P 5-kinase. Biochem J 309(Pt 3):715–719Google Scholar
  40. Domin J, Gaidarov I, Smith ME et al (2000) The class II phosphoinositide 3-kinase PI3K-C2alpha is concentrated in the trans-Golgi network and present in clathrin-coated vesicles. J Biol Chem 275:11943–11950PubMedGoogle Scholar
  41. Dominguez V, Raimondi C, Somanath S et al (2010) Class II phosphoinositide 3-kinase regulates exocytosis of insulin granules in pancreatic beta cells. J Biol Chem 1–22: . doi: 10.1074/jbc.M110.200295 Google Scholar
  42. Dove SK, Piper RC, McEwen RK et al (2004) Svp1p defines a family of phosphatidylinositol 3,5-bisphosphate effectors. EMBO J 23:1922–1933. doi: 10.1038/sj.emboj.7600203 7600203 [pii]PubMedGoogle Scholar
  43. Downes CP, Gray A, Lucocq JM (2005) Probing phosphoinositide functions in signaling and membrane trafficking. Trends Cell Biol 15:259–268. doi: 10.1016/j.tcb.2005.03.008 PubMedGoogle Scholar
  44. Duckworth WC, Solomon SS, Liepnieks J et al (1988) Insulin-like effects of vanadate in isolated rat adipocytes. Endocrinology 122:2285–2289PubMedGoogle Scholar
  45. Duex JE, Nau J, Kauffman E, Weisman LS (2006a) Phosphoinositide 5-phosphatase Fig4p Is required for both acute rise and subsequent fall in stress-induced phosphatidylinositol 3,5-bisphosphate levels. Eukaryot Cell 5:723–731PubMedGoogle Scholar
  46. Duex JE, Tang F, Weisman LS (2006b) The Vac14p-Fig4p complex acts independently of Vac7p and couples PI3,5P2 synthesis and turnover. J Cell Biol 172:693–704PubMedGoogle Scholar
  47. Efe J, Botelho RJ, Emr SD (2007) Atg18 regulates organelle morphology and Fab1 kinase activity independent of its membrane recruitment by phosphatidylinositol 3,5-bisphosphate. Mol Biol Cell 18:4232–4244PubMedGoogle Scholar
  48. Eguez L, Lee A, Chavez JA et al (2005) Full intracellular retention of GLUT4 requires AS160 Rab GTPase activating protein. Cell Metab 2:263–272. doi: 10.1016/j.cmet.2005.09.005 PubMedGoogle Scholar
  49. Erneux C, Edimo WE, Deneubourg L, Pirson I (2011) SHIP2 multiple functions: a balance between a negative control of PtdIns(3,4,5)P(3) level, a positive control of PtdIns(3,4)P(2) production, and intrinsic docking properties. J Cell Biochem 112:2203–2209. doi: 10.1002/jcb.23146 PubMedGoogle Scholar
  50. Falasca M, Hughes WE, Dominguez V et al (2007) The role of phosphoinositide 3-kinase C2alpha in insulin signaling. J Biol Chem 282:28226–28236. doi: 10.1074/jbc.M704357200 PubMedGoogle Scholar
  51. Fang Y, Vilella-Bach M, Bachmann R et al (2001) Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science (New York, NY) 294:1942–1945. doi: 10.1126/science.1066015
  52. Fang Y, Park I-H, Wu A-L et al (2003) PLD1 regulates mTOR signaling and mediates Cdc42 activation of S6K1. Curr Biol 13:2037–2044. doi: 10.1016/j.cub.2003.11.021 PubMedGoogle Scholar
  53. Fedele CG, Ooms LM, Ho M et al (2010) Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc Natl Acad Sci U S A 107:22231–22236. doi: 10.1073/pnas.1015245107 PubMedGoogle Scholar
  54. Fisher JS, Nolte LA, Kawanaka K et al (2002) Glucose transport rate and glycogen synthase activity both limit skeletal muscle glycogen accumulation. Am J Physiol Endocrinol Metab 282:E1214–E1221. doi: 10.1152/ajpendo.00254.2001 PubMedGoogle Scholar
  55. Foley K, Boguslavsky S, Klip A (2011) Endocytosis, recycling and regulated exocytosis of glucose transporter 4 (GLUT4). Biochemistry. doi: 10.1021/bi2000356 PubMedGoogle Scholar
  56. Foti M, Audhya A, Emr SD (2001) Sac1 lipid phosphatase and Stt4 phosphatidylinositol 4-kinase regulate a pool of phosphatidylinositol 4-phosphate that functions in the control of the actin cytoskeleton and vacuole morphology. Mol Biol Cell 12:2396–2411PubMedGoogle Scholar
  57. Foukas LC, Claret M, Pearce W et al (2006) Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441:366–370. doi: 10.1038/nature04694 PubMedGoogle Scholar
  58. Franke TF, Yang SI, Chan TO et al (1995) The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81:727–736PubMedGoogle Scholar
  59. Gaidarov I, Smith ME, Domin J, Keen JH (2001) The class II phosphoinositide 3-kinase C2alpha is activated by clathrin and regulates clathrin-mediated membrane trafficking. Mol Cell 7:443–449PubMedGoogle Scholar
  60. Gary JD, Wurmser AE, Bonangelino C et al (1998) Fab1p is essential for PtdIns(3)P 5-kinase activity and the maintenance of vacuolar size and membrane homeostasis. J Cell Biol 143:65–79PubMedGoogle Scholar
  61. Gary J, Sato T, Stefan C et al (2002) Regulation of Fab1 phosphatidylinositol 3-phosphate 5-kinase pathway by Vac7 protein and Fig4, a polyphosphoinositide phosphatase family member. Mol Biol Cell 13:1238–1251PubMedGoogle Scholar
  62. Gewinner C, Wang ZC, Richardson A et al (2009) Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 16:115–125. doi: 10.1016/j.ccr.2009.06.006 PubMedGoogle Scholar
  63. Gonzalez E, McGraw TE (2009) Insulin-modulated Akt subcellular localization determines Akt isoform-specific signaling. Proc Natl Acad Sci U S A 106:7004–7009. doi: 10.1073/pnas.0901933106 PubMedGoogle Scholar
  64. Green CJ, Göransson O, Kular GS et al (2008) Use of Akt inhibitor and a drug-resistant mutant validates a critical role for protein kinase B/Akt in the insulin-dependent regulation of glucose and system A amino acid uptake. J Biol Chem 283:27653–27667. doi: 10.1074/jbc.M802623200 PubMedGoogle Scholar
  65. Gridley S, Chavez JA, Lane WS, Lienhard GE (2006) Adipocytes contain a novel complex similar to the tuberous sclerosis complex. Cell Signal 18:1626–1632. doi: 10.1016/j.cellsig.2006.01.002 PubMedGoogle Scholar
  66. Guo J-P, Coppola D, Cheng JQ (2011) IKBKE activates Akt independent of phosphatidylinositol 3-kinase/PDK1/mTORC2 and PH domain to sustain malignant transformation. J Biol Chem. doi: 10.1074/jbc.M111.287433 Google Scholar
  67. Gurung R, Tan A, Ooms LM et al (2003) Identification of a novel domain in two mammalian inositol-polyphosphate 5-phosphatases that mediates membrane ruffle localization. The inositol 5-phosphatase skip localizes to the endoplasmic reticulum and translocates to membrane ruffles following epide. J Biol Chem 278:11376–11385. doi: 10.1074/jbc.M209991200 PubMedGoogle Scholar
  68. Habib T, Hejna JA, Moses RE, Decker SJ (1998) Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein. J Biol Chem 273:18605–18609PubMedGoogle Scholar
  69. He B, Xi F, Zhang X et al (2007) Exo70 interacts with phospholipids and mediates the targeting of the exocyst to the plasma membrane. EMBO J 26:4053–4065. doi: 10.1038/sj.emboj.7601834 PubMedGoogle Scholar
  70. Horie Y, Suzuki A, Kataoka E et al (2004) Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Investig. doi: 10.1172/JCI200420513.1774 PubMedGoogle Scholar
  71. Huffman TA, Mothe-Satney I, Lawrence JJC (2002) Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin. Proc Natl Acad Sci U S A 99:1047–1052PubMedGoogle Scholar
  72. Ijuin T, Takenawa T (2003) SKIP negatively regulates insulin-induced GLUT4 translocation and membrane ruffle formation. Mol Cell Biol 23:1209–1220. doi: 10.1128/MCB.23.4.1209 PubMedGoogle Scholar
  73. Ijuin T, Takenawa T (2012) Regulation of insulin signalling and glucose transporter 4 (GLUT4) exocytosis by the phosphatidylinositol 3,4,5-trisphosphate (PIP3) phosphatase, SKIP. J Biol Chem. doi: 10.1074/jbc.M111.335539 Google Scholar
  74. Ijuin T, Yu YE, Mizutani K et al (2008) Increased insulin action in SKIP heterozygous knockout mice. Mol Cell Biol 28:5184–5195. doi: 10.1128/MCB.01990-06 PubMedGoogle Scholar
  75. Ikonomov OC, Sbrissa D, Mlak K, Shisheva A (2002) Requirement for PIKfyve enzymatic activity in acute and long-term insulin cellular effects. Endocrinology 143:4742–4754PubMedGoogle Scholar
  76. Ikonomov OC, Sbrissa D, Dondapati R, Shisheva A (2007) ArPIKfyve-PIKfyve interaction and role in insulin-regulated GLUT4 translocation and glucose transport in 3T3-L1 adipocytes. Exp Cell Res 313:2404–2416. doi: 10.1016/j.yexcr.2007.03.024 S0014-4827(07)00113-9 [pii]PubMedGoogle Scholar
  77. Ikonomov OC, Sbrissa D, Ijuin T et al (2009) Sac3 is an Insulin-regulated PtdIns(3,5)P2 phosphatase: gain in insulin responsiveness through Sac3 downregulation in adipocytes. J Biol Chem. doi: 10.1074/jbc.M109.025361. M109.025361 [pii]
  78. Ikonomov OC, Sbrissa D, Fligger J et al (2010) ArPIKfyve regulates Sac3 protein abundance and turnover: disruption of the mechanism by Sac3I41T mutation causing Charcot-Marie-Tooth 4J disorder. J Biol Chem. doi: 10.1074/jbc.C110.154658 PubMedGoogle Scholar
  79. Ikonomov OC, Sbrissa D, Delvecchio K et al (2011) The phosphoinositide kinase PIKfyve is vital in early embryonic development: preimplantation lethality of PIKfyve−/− embryos but normality of PIKfyve+/− mice. J Biol Chem 286:13404–13413. doi: 10.1074/jbc.M111.222364 PubMedGoogle Scholar
  80. Inoki K, Li Y, Zhu T et al (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657. doi: 10.1038/ncb839 ncb839 [pii]PubMedGoogle Scholar
  81. Inoki K, Li Y, Xu T, Guan K-L (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17:1829–1834. doi: 10.1101/gad.1110003 PubMedGoogle Scholar
  82. Inoue M, Chang L, Hwang J et al (2003) The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin. Nature 422:629–633. doi: 10.1038/nature01533 nature01533 [pii]PubMedGoogle Scholar
  83. Inoue M, Chiang SH, Chang L et al (2006) Compartmentalization of the exocyst complex in lipid rafts controls Glut4 vesicle tethering. Mol Biol Cell 17:2303–2311. doi: 10.1091/mbc.E06-01-0030 E06-01-0030 [pii]PubMedGoogle Scholar
  84. Ishiki M, Randhawa VK, Poon V et al (2005) Insulin regulates the membrane arrival, fusion, and C-terminal unmasking of glucose transporter-4 via distinct phosphoinositides. J Biol Chem 280:28792–28802. doi: 10.1074/jbc.M500501200 PubMedGoogle Scholar
  85. James SR, Downes CP, Gigg R et al (1996) Specific binding of the Akt-1 protein kinase to phosphatidylinositol 3,4,5-trisphosphate without subsequent activation. Biochem J 315(Pt 3):709–713Google Scholar
  86. James DJ, Khodthong C, Kowalchyk JA, Martin TFJ (2008) Phosphatidylinositol 4,5-bisphosphate regulates SNARE-dependent membrane fusion. J Cell Biol 182:355–366. doi: 10.1083/jcb.200801056 PubMedGoogle Scholar
  87. Jia S, Liu Z, Zhang S et al (2008) Essential roles of PI (3) K—p110b in cell growth, metabolism and tumorigenesis. Nature. doi: 10.1038/nature07091 Google Scholar
  88. Jiang ZY, Zhou QL, Coleman KA et al (2003) Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing. Proc Natl Acad Sci U S A 100:7569–7574. doi: 10.1073/pnas.1332633100 PubMedGoogle Scholar
  89. Jin N, Chow CY, Liu L et al (2008) VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse. EMBO J 27:3221–3234. doi: 10.1038/emboj.2008.248 emboj2008248 [pii]PubMedGoogle Scholar
  90. Jones DR, Bultsma Y, Keune W-J et al (2006) Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kbeta. Mol Cell 23:685–695. doi: 10.1016/j.molcel.2006.07.014 PubMedGoogle Scholar
  91. Kanai F, Ito K, Todaka M et al (1993) Insulin-stimulated GLUT4 translocation is relevant to the phosphorylation of IRS-1 and the activity of PI3-kinase. Biochem Biophys Res Commun 195:762–768. doi: 10.1006/bbrc.1993.2111 PubMedGoogle Scholar
  92. Khwaja A, Rodriguez-Viciana P, Wennström S et al (1997) Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J 16:2783–2793. doi: 10.1093/emboj/16.10.2783 PubMedGoogle Scholar
  93. Kihara A, Noda T, Ishihara N, Ohsumi Y (2001) Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol 152:519–530PubMedGoogle Scholar
  94. Kim E, Goraksha-Hicks P, Li L et al (2008) Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10:935–945. doi: 10.1038/ncb1753 ncb1753 [pii]PubMedGoogle Scholar
  95. Knobbe CB, Lapin V, Suzuki A, Mak TW (2008) The roles of PTEN in development, physiology and tumorigenesis in mouse models: a tissue-by-tissue survey. Oncogene 27:5398–5415. doi: 10.1038/onc.2008.238 PubMedGoogle Scholar
  96. Kong AM, Horan KA, Sriratana A et al (2006) Phosphatidylinositol 3-phosphate [PtdIns3P] is generated at the plasma membrane by an inositol polyphosphate 5-phosphatase: endogenous PtdIns3P can promote GLUT4 translocation to the plasma membrane. Mol Cell Biol 26:6065–6081. doi: 10.1128/MCB.00203-06 PubMedGoogle Scholar
  97. Kurlawalla-Martinez C, Stiles B, Wang Y et al (2005) Insulin hypersensitivity and resistance to streptozotocin-induced diabetes in mice lacking PTEN in adipose tissue. Mol Cell Biol 25:2498–2510. doi: 10.1128/MCB.25.6.2498-2510.2005 PubMedGoogle Scholar
  98. Kurosu H, Katada T (2001) Association of phosphatidylinositol 3-kinase composed of p110beta-catalytic and p85-regulatory subunits with the small GTPase Rab5. J Biochem 130:73–78PubMedGoogle Scholar
  99. Laplante M, Sabatini DM (2010) mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis. Proc Natl Acad Sci U S A 107:3281–3282. doi: 10.1073/pnas.1000323107 PubMedGoogle Scholar
  100. Lawrence JTR, Birnbaum MJ (2003) ADP-ribosylation factor 6 regulates insulin secretion through plasma membrane phosphatidylinositol 4,5-bisphosphate. Proc Natl Acad Sci U S A 100:13320–13325. doi: 10.1073/pnas.2232129100 PubMedGoogle Scholar
  101. Le Marchand-Brustel Y, Gautier N, Cormont M, Van Obberghen E (1995) Wortmannin inhibits the action of insulin but not that of okadaic acid in skeletal muscle: comparison with fat cells. Endocrinology 136:3564–3570PubMedGoogle Scholar
  102. Li J, Yen C, Liaw D et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science (New York, NY) 275:1943–1947Google Scholar
  103. Liu J, Zuo X, Yue P, Guo W (2007) Phosphatidylinositol 4, 5-bisphosphate mediates the targeting of the Exocyst to the plasma membrane for exocytosis in mammalian cells. Mol Biol Cell 18:4483–4492. doi: 10.1091/mbc.E07 PubMedGoogle Scholar
  104. Lodhi I, Bridges D, Chiang S-H et al (2008) Insulin stimulates phosphatidylinositol 3-phosphate production via the activation of Rab5. Mol Biol Cell. doi:10.1091/mbc.E08-01-0105Google Scholar
  105. Maehama T, Dixon J (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273:13375–13378PubMedGoogle Scholar
  106. Maffucci T, Brancaccio A, Piccolo E et al (2003) Insulin induces phosphatidylinositol-3-phosphate formation through TC10 activation. EMBO J 22:4178–4189. doi: 10.1093/emboj/cdg402 PubMedGoogle Scholar
  107. Manning BD, Tee AR, Logsdon MN et al (2002) Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 10:151–162Google Scholar
  108. Mao Y, Balkin DM, Zoncu R et al (2009) A PH domain within OCRL bridges clathrin-mediated membrane trafficking to phosphoinositide metabolism. EMBO J 28:1831–1842. doi: 10.1038/emboj.2009.155 PubMedGoogle Scholar
  109. Mazza S, Maffucci T (2011) Class II phosphoinositide 3-kinase C2alpha: what we learned so far. J Biochem Mol Biol 2:168–182Google Scholar
  110. McManus EJ, Collins BJ, Ashby PR et al (2004) The in vivo role of PtdIns(3,4,5)P3 binding to PDK1 PH domain defined by knockin mutation. EMBO J 23:2071–2082. doi: 10.1038/sj.emboj.7600218 PubMedGoogle Scholar
  111. Mellor P, Furber LA, Nyarko JNK, Anderson DH (2012) Multiple roles for the p85α isoform in the regulation and function of PI3K signalling and receptor trafficking. Biochem J 441:23–37. doi: 10.1042/BJ20111164 PubMedGoogle Scholar
  112. Meunier FA, Osborne SL, Hammond GRV et al (2005) Phosphatidylinositol 3-kinase C2alpha is essential for ATP-dependent priming of neurosecretory granule exocytosis. Mol Biol Cell 16:4841–4851. doi: 10.1091/mbc.E05-02-0171 PubMedGoogle Scholar
  113. Miaczynska M, Christoforidis S, Giner A et al (2004) APPL proteins link Rab5 to nuclear signal transduction via an endosomal compartment. Cell 116:445–456PubMedGoogle Scholar
  114. Michael MD, Kulkarni RN, Postic C et al (2000) Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 6:87–97PubMedGoogle Scholar
  115. Mima J, Wickner W (2009) Phosphoinositides and SNARE chaperones synergistically assemble and remodel SNARE complexes for membrane fusion. Proc Natl Acad Sci U S A 106:16191–16196PubMedGoogle Scholar
  116. Ng Y, Ramm G, Lopez JA, James DE (2008) Rapid activation of Akt2 is sufficient to stimulate GLUT4 translocation in 3T3-L1 adipocytes. Cell Metab 7:348–356. doi: 10.1016/j.cmet.2008.02.008 PubMedGoogle Scholar
  117. Nguyen K-TT, Tajmir P, Lin CH et al (2006) Essential role of Pten in body size determination and pancreatic beta-cell homeostasis in vivo. Mol Cell Biol 26:4511–4518. doi: 10.1128/MCB.00238-06 PubMedGoogle Scholar
  118. Nicot A-S, Laporte J (2008) Endosomal phosphoinositides and human diseases. Traffic (Copenhagen, Denmark) 9:1240–1249Google Scholar
  119. Nobukuni T, Joaquin M, Roccio M et al (2005) Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci U S A 102:14238–14243. doi: 10.1073/pnas.0506925102 PubMedGoogle Scholar
  120. Nolte LA, Han D-H, Hansen PA et al (2003) A peroxovanadium compound stimulates muscle glucose transport as powerfully as insulin and contractions combined. Diabetes 52:1918–1925PubMedGoogle Scholar
  121. Norris FA, Auethavekiat V, Majerus PW (1995) The isolation and characterization of cDNA encoding human and rat brain inositol polyphosphate 4-phosphatase. J Biol Chem 270:16128–16133PubMedGoogle Scholar
  122. Norris FA, Atkins RC, Majerus PW (1997) The cDNA cloning and characterization of inositol polyphosphate 4-phosphatase type II. Evidence for conserved alternative splicing in the 4-phosphatase family. J Biol Chem 272:23859–23864PubMedGoogle Scholar
  123. Okada T, Kawano Y, Sakakibara T et al (1994) Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. J Biol Chem 269:3568–3573PubMedGoogle Scholar
  124. Okada S, Ohshima K, Uehara Y et al (2007) Synip phosphorylation is required for insulin-stimulated Glut4 translocation. Biochem Biophys Res Commun 356:102–106. doi: 10.1016/j.bbrc.2007.02.095 PubMedGoogle Scholar
  125. Olsen HL, Hoy M, Zhang W et al (2003) Phosphatidylinositol 4-kinase serves as a metabolic sensor and regulates priming of secretory granules in pancreatic beta cells. Proc Natl Acad Sci U S A 100:5187–5192. doi: 10.1073/pnas.0931282100 PubMedGoogle Scholar
  126. Ooms LM, Horan KA, Rahman P et al (2009) The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem J 419:29–49. doi: 10.1042/BJ20081673 PubMedGoogle Scholar
  127. Ou Y-H, Torres M, Ram R et al (2011) TBK1 directly engages Akt/PKB survival signaling to support oncogenic transformation. Mol Cell 41:458–470. doi: 10.1016/j.molcel.2011.01.019 PubMedGoogle Scholar
  128. Patton GM, Fasulo JM, Robins SJ (1982) Separation of phospholipids and individual molecular species of phospholipids by high-performance liquid chromatography. J Lipid Res 23:190–196PubMedGoogle Scholar
  129. Peterson TRR, Sengupta SSS, Harris TEE et al (2011) mTOR complex 1 regulates Lipin 1 localization to control the SREBP pathway. Cell 146:408–420. doi: 10.1016/j.cell.2011.06.034 PubMedGoogle Scholar
  130. Petritsch C, Woscholski R, Edelmann HM et al (1995) Selective inhibition of p70 S6 kinase activation by phosphatidylinositol 3-kinase inhibitors. Eur J Biochem/FEBS 230:431–438Google Scholar
  131. Podsypanina K, Ellenson LH, Nemes A et al (1999) Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A 96:1563–1568PubMedGoogle Scholar
  132. Prasad NK, Werner ME, Decker SJ (2009) Specific tyrosine phosphorylations mediate signal-dependent stimulation of SHIP2 inositol phosphatase activity, while the SH2 domain confers an inhibitory effect to maintain the basal activity. Biochemistry 48:6285–6287. doi: 10.1021/bi900492d PubMedGoogle Scholar
  133. Rabinovsky R, Pochanard P, McNear C et al (2009) p85 Associates with unphosphorylated PTEN and the PTEN-associated complex. Mol Cell Biol 29:5377–5388. doi: 10.1128/MCB.01649-08 PubMedGoogle Scholar
  134. Rameh LE, Tolias KF, Duckworth BC, Cantley LC (1997) A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate. Nature 390:192–196. doi: 10.1038/36621 PubMedGoogle Scholar
  135. Rodriguez-Viciana P, Warne PH, Dhand R et al (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370:527–532. doi: 10.1038/370527a0 PubMedGoogle Scholar
  136. Rommel C, Bodine SC, Clarke BA et al (2001) Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol 3:1009–1013. doi: 10.1038/ncb1101-1009 PubMedGoogle Scholar
  137. Rosivatz E, Matthews JG, McDonald NQ et al (2006) A small molecule inhibitor for phosphatase and tensin homologue deleted on chromosome 10 (PTEN). ACS Chem Biol 1:780–790. doi: 10.1021/cb600352f PubMedGoogle Scholar
  138. Rowland AF, Fazakerley DJ, James DE (2011) Mapping insulin/GLUT4 circuitry. traffic (Copenhagen, Denmark). doi: 10.1111/j.1600-0854.2011.01178.x
  139. Rudge S, Anderson DH, Emr SD (2004) Vacuole size control: regulation of PtdIns(3,5)P2 levels by the vacuole-associated Vac14-Fig4 complex, a PtdIns(3,5)P2-specific phosphatase. Mol Biol Cell 15:24–36PubMedGoogle Scholar
  140. Saito T, Jones CC, Huang S et al (2007) The interaction of Akt with APPL1 is required for insulin-stimulated Glut4 translocation. J Biol Chem 282:32280–32287. doi: 10.1074/jbc.M704150200 PubMedGoogle Scholar
  141. Sancak Y, Peterson TR, Shaul YD et al (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science (New York, NY) 320:1496–1501Google Scholar
  142. Sancak Y, Bar-Peled L, Zoncu R et al (2010) Ragulator-rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303PubMedGoogle Scholar
  143. Sano H, Kane S, Sano E et al (2003) Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem 278:14599–14602. doi: 10.1074/jbc.C300063200 PubMedGoogle Scholar
  144. Sano H, Kane S, Sano E, Lienhard GE (2005) Synip phosphorylation does not regulate insulin-stimulated GLUT4 translocation. Biochem Biophys Res Commun 332:880–884. doi: 10.1016/j.bbrc.2005.05.027 PubMedGoogle Scholar
  145. Sano H, Eguez L, Teruel MN et al (2007) Rab10, a target of the AS160 Rab GAP, is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane. Cell Metab 5:293–303. doi: 10.1016/j.cmet.2007.03.001 PubMedGoogle Scholar
  146. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science (New York, NY) 307:1098–1101. doi: 10.1126/science.1106148
  147. Sarkes D, Rameh LE (2010) A novel HPLC-based approach makes possible the spacial characterization of cellular PtdIns5P and other phosphoinositides. Biochem J 384:375–384. doi: 10.1042/BJ20100129 Google Scholar
  148. Sbrissa D, Shisheva A (2005) Acquisition of unprecedented phosphatidylinositol 3,5-bisphosphate rise in hyperosmotically stressed 3T3-L1 adipocytes, mediated by ArPIKfyve-PIKfyve pathway. J Biol Chem 280:7883–7889. doi: 10.1074/jbc.M412729200 M412729200 [pii]PubMedGoogle Scholar
  149. Sbrissa D, Ikonomov OC, Shisheva A (1999) PIKfyve, a mammalian ortholog of yeast Fab1p lipid kinase, synthesizes 5-phosphoinositides. Effect of insulin. J Biol Chem 274:21589–21597PubMedGoogle Scholar
  150. Sbrissa D, Ikonomov OC, Strakova J, Shisheva A (2004) Role for a novel signaling intermediate, phosphatidylinositol 5-phosphate, in insulin-regulated F-actin stress fiber breakdown and GLUT4 translocation. Endocrinology 145:4853–4865. doi: 10.1210/en.2004-0489 PubMedGoogle Scholar
  151. Sbrissa D, Ikonomov OC, Fu Z et al (2007) Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex. J Biol Chem 282:23878–23891. doi: 10.1074/jbc.M611678200 M611678200 [pii]PubMedGoogle Scholar
  152. Sbrissa D, Ikonomov OC, Fenner H, Shisheva A (2008) ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality. J Mol Biol 384:766–779PubMedGoogle Scholar
  153. Schenck A, Goto-Silva L, Collinet C et al (2008) The endosomal protein App l1 mediates Akt substrate specificity and cell survival in vertebrate development. Cell 133:486–497. doi: 10.1016/j.cell.2008.02.044 PubMedGoogle Scholar
  154. Schmid AC, Byrne RD, Vilar R, Woscholski R (2004) Bisperoxovanadium compounds are potent PTEN inhibitors. FEBS Lett 566:35–38. doi: 10.1016/j.febslet.2004.03.102 PubMedGoogle Scholar
  155. Schu PV, Takegawa K, Fry MJ et al (1993) Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science (New York, NY) 260:88–91Google Scholar
  156. Shepherd PR, Navé BT, Siddle K (1995) Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin and rapamycin in 3T3-L1 adipocytes: evidence for the involvement of phosphoinositide 3-kinase and p70 ribosomal protein-S6 kinase. Biochem J 305(Pt 1):25–28Google Scholar
  157. Shin HW, Hayashi M, Christoforidis S et al (2005) An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway. J Cell Biol 170:607–618. doi: 10.1083/jcb.200505128 jcb.200505128 [pii]PubMedGoogle Scholar
  158. Sleeman MW, Wortley KE, Lai K-MV et al (2005) Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity. Nat Med 11:199–205. doi: 10.1038/nm1178 PubMedGoogle Scholar
  159. Sopasakis VR, Liu P, Suzuki R et al (2010) Specific roles of the p110a isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation. Cell Metab 11:220–230. doi: 10.1016/j.cmet.2010.02.002 PubMedGoogle Scholar
  160. Staal SP, Hartley JW (1988) Thymic lymphoma induction by the AKT8 murine retrovirus. J Exp Med 167:1259–1264PubMedGoogle Scholar
  161. Stahelin R, Ananthanarayanan B, Blatner N et al (2004) Mechanism of membrane binding of the phospholipase D1 PX domain. J Biol Chem 279:54918–54926PubMedGoogle Scholar
  162. Steck PA, Pershouse MA, Jasser SA et al (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362. doi: 10.1038/ng0497-356 PubMedGoogle Scholar
  163. Stiles B, Wang Y, Stahl A et al (2004) Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. Proc Natl Acad Sci U S A 101:2082–2087. doi: 10.1073/pnas.0308617100 PubMedGoogle Scholar
  164. Stiles BL, Kuralwalla-Martinez C, Guo W et al (2006) Selective deletion of Pten in pancreatic beta cells leads to increased islet mass and resistance to STZ-induced diabetes. Mol Cell Biol 26:2772. doi: 10.1128/MCB.26.7.2772 PubMedGoogle Scholar
  165. Sun Y, Bilan PJ, Liu Z, Klip A (2010) Rab8A and Rab13 are activated by insulin and regulate GLUT4 translocation in muscle cells. Proc Natl Acad Sci U S A 2010:6–11. doi: 10.1073/pnas.1009523107 Google Scholar
  166. Suwa A, Yamamoto T, Sawada A et al (2009) Discovery and functional characterization of a novel small molecule inhibitor of the intracellular phosphatase, SHIP2. Br J Pharmacol 158:879–887. doi: 10.1111/j.1476-5381.2009.00358.x PubMedGoogle Scholar
  167. Suzuki A, De la Pompa JL, Stambolic V et al (1998) High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol CB 8:1169–1178Google Scholar
  168. Tan Y, You H, Wu C et al (2010) App l1 is dispensable for mouse development, and loss of Appl1 has growth factor-selective effects on Akt signaling in murine embryonic fibroblasts. J Biol Chem 285:6377–6389. doi: 10.1074/jbc.M109.068452 PubMedGoogle Scholar
  169. Tan S-X, Ng Y, James DE (2011) Next generation Akt inhibitors provide greater specificity-effects on glucose metabolism in adipocytes. Biochem J. doi: 10.1042/BJ20110040 Google Scholar
  170. Tee AR, Manning BD, Roux PP et al (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 13:1259–1268PubMedGoogle Scholar
  171. Vanhaesebroeck B, Stephens L, Hawkins P (2012) PI3K signalling: the path to discovery and understanding. Nat Rev Mol Cell Biol 13:195–203. doi: 10.1038/nrm3290 PubMedGoogle Scholar
  172. Vicinanza M, Campli AD, Polishchuk E et al (2011) OCRL controls trafficking through early regulation of endosomal actin. EMBO J 1–16: . doi: 10.1038/emboj.2011.354 Google Scholar
  173. Vicogne J, Vollenweider D, Smith JR et al (2006) Asymmetric phospholipid distribution drives in vitro reconstituted SNARE-dependent membrane fusion. Proc Natl Acad Sci U S A 103:14761–14766. doi: 10.1073/pnas.0606881103 PubMedGoogle Scholar
  174. Wada T, Sasaoka T, Funaki M et al (2001) Overexpression of SH2-containing inositol phosphatase 2 results in negative regulation of insulin-induced metabolic actions in 3T3-L1 adipocytes via its 5′-phosphatase catalytic activity. Mol Cell Biol 21:1633–1646. doi: 10.1128/MCB.21.5.1633-1646.2001 PubMedGoogle Scholar
  175. Waselle L, Gerona RRL, Vitale N et al (2005) Role of phosphoinositide signaling in the control of insulin exocytosis. Mol Endocrinol (Baltimore, Md) 19:3097–3106. doi: 10.1210/me.2004-0530 Google Scholar
  176. Wen PJ, Osborne SL, Morrow IC et al (2008) Ca2+-regulated pool of phosphatidylinositol-3-phosphate produced by phosphatidylinositol 3-kinase C2alpha on neurosecretory vesicles. Mol Biol Cell 19:5593–5603. doi: 10.1091/mbc.E08-06-0595 PubMedGoogle Scholar
  177. Weng QP, Andrabi K, Kozlowski MT et al (1995) Multiple independent inputs are required for activation of the p70 S6 kinase. Mol Cell Biol 15:2333–2340PubMedGoogle Scholar
  178. Westergaard N, Brand CL, Lewinsky RH et al (1999) Peroxyvanadium compounds inhibit glucose-6-phosphatase activity and glucagon-stimulated hepatic glucose output in the rat in vivo. Arch Biochem Biophys 366:55–60. doi: 10.1006/abbi.1999.1181 PubMedGoogle Scholar
  179. Wijesekara N, Konrad D, Eweida M et al (2005) Muscle-specific Pten deletion protects against insulin resistance and diabetes. Society 25:1135–1145. doi: 10.1128/MCB.25.3.1135 Google Scholar
  180. Williams C, Choudhury R, McKenzie E, Lowe M (2007) Targeting of the type II inositol polyphosphate 5-phosphatase INPP5B to the early secretory pathway. J Cell Sci 120:3941–3951. doi: 10.1242/jcs.014423 PubMedGoogle Scholar
  181. Wong JT, Kim PTW, Peacock JW et al (2007) Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity. Diabetologia 50:395–403. doi: 10.1007/s00125-006-0531-x PubMedGoogle Scholar
  182. Wong K-K, Engelman JA, Cantley LC (2010) Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 20:87–90. doi: 10.1016/j.gde.2009.11.002 PubMedGoogle Scholar
  183. Wymann MP, Björklöf K, Calvez R et al (2003) Phosphoinositide 3-kinase gamma: a key modulator in inflammation and allergy. Biochem Soc Trans 31:275–280. doi: 10.1042/ PubMedGoogle Scholar
  184. Xie X, Gong Z, Mansuy-Aubert V et al (2011a) C2 domain-containing phosphoprotein CDP138 regulates GLUT4 insertion into the plasma membrane. Cell Metab 14:378–389. doi: 10.1016/j.cmet.2011.06.015 PubMedGoogle Scholar
  185. Xie X, Zhang D, Zhao B et al (2011b) I{kappa}B kinase varepsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A. doi: 10.1073/pnas.1016132108 Google Scholar
  186. Xiong Q, Deng C-Y, Chai J et al (2009) Knockdown of endogenous SKIP gene enhanced insulin-induced glycogen synthesis signaling in differentiating C2C12 myoblasts. BMB Rep 42:119–124PubMedGoogle Scholar
  187. Xu L, Salloum D, Medlin PS et al (2011) Phospholipase D mediates nutrient input to mTORC1. J Biol Chem 286:25477–25486. doi: 10.1074/jbc.M111.249631 PubMedGoogle Scholar
  188. Yamada E, Okada S, Saito T et al (2005) Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. J Cell Biol 168:921–928. doi: 10.1083/jcb.200408182 PubMedGoogle Scholar
  189. Yamashita M, Kurokawa K, Sato Y et al (2010) Structural basis for the Rho- and phosphoinositide-dependent localization of the exocyst subunit Sec3. Nat Struct Mol Biol 17:180–186. doi: 10.1038/nsmb.1722 PubMedGoogle Scholar
  190. Yecies JL, Zhang HH, Menon S et al (2011) Akt stimulates hepatic SREBP1c and Lipogenesis through Parallel mTORC1-Dependent and Independent Pathways. Cell Metab 14:21–32. doi: 10.1016/j.cmet.2011.06.002 PubMedGoogle Scholar
  191. Yoon M-S, Du G, Backer JM et al (2011) Class III PI-3-kinase activates phospholipase D in an amino acid-sensing mTORC1 pathway. J Cell Biol. doi: 10.1083/jcb.201107033 Google Scholar
  192. Yu JW, Lemmon MA (2001) All phox homology (PX) domains from Saccharomyces cerevisiae specifically recognize phosphatidylinositol 3-phosphate. J Biol Chem 276:44179–44184. doi: 10.1074/jbc.M108811200 PubMedGoogle Scholar
  193. Yu ZW, Jansson PA, Posner BI et al (1997) Peroxovanadate and insulin action in adipocytes from NIDDM patients. Evidence against a primary defect in tyrosine phosphorylation. Diabetologia 40:1197–1203. doi: 10.1007/s001250050807 PubMedGoogle Scholar
  194. Yuan Y, Gao X, Guo N et al (2007) rSac3, a novel Sac domain phosphoinositide phosphatase, promotes neurite outgrowth in PC12 cells. Cell Res 17:919–932. doi: 10.1038/cr.2007.82 PubMedGoogle Scholar
  195. Zhang X, Loijens JC, Boronenkov IV et al (1997) Phosphatidylinositol-4-phosphate 5-kinase isozymes catalyze the synthesis of 3-phosphate-containing phosphatidylinositol signaling molecules. J Biol Chem 272:17756–17761PubMedGoogle Scholar
  196. Zhang Y, Zolov SN, Chow C et al (2007) Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice. Proc Natl Acad Sci 104:17518–17523PubMedGoogle Scholar
  197. Zisman A, Peroni OD, Abel ED et al (2000) Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med 6:924–928. doi: 10.1038/78693 PubMedGoogle Scholar
  198. Zoncu R, Perera RM, Balkin DM et al (2009) A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes. Cell 136:1110–1121. doi: 10.1016/j.cell.2009.01.032 S0092-8674(09)00080-4 [pii]PubMedGoogle Scholar
  199. Zoncu R, Bar-Peled L, Efeyan A et al (2011) mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science (New York, NY) 334:678–683. doi: 10.1126/science.1207056
  200. Zurita-Martinez SA, Puria R, Pan X et al (2007) Efficient Tor signaling requires a functional class C Vps protein complex in Saccharomyces cerevisiae. Genetics 176:2139–2150PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  1. 1.Life Sciences Institute, University of MichiganAnn ArborUSA

Personalised recommendations