Signal Transduction

Table 18.1  Protooncogenes and tumour suppressors associated with the mTOR/Raptor (mTORC1) signalling pathway

Protooncogenes functionally linked to mTORC1 signalling

That the understanding of how tumours arise is impressive yet still limited is given by the observation that mice lacking PTP1B exhibit no predisposition to cancer. This, despite the fact that this phosphatase has a central place in the deactivation of the insulin receptor and that when absent, the PKB signalling pathway is strongly enhanced. These mice are highly responsive to insulin and show little propensity to obesity (see page 648).86

Other processes mediated by the 3-phosphorylated inositol phospholipids

A number of seemingly disparate functions are modified in cells and organisms in which the synthesis of the 3-phosphorylated lipids is chronically altered (see Figure 18.1). These include

566

Phosphoinositide 3-Kinases, Protein Kinase B, and Signalling through Insulin Receptor

So, who did discover insulin?

Probably nobody discovered insulin. It existed first as an idea (Minkowski), then as a proven hypothesis (Gley and others), and finally as a practical way of alleviating diabetes (Paulescu and Banting) (adapted from Henderson3).

List of abbreviations

Continued

567

Signal Transduction

Continued

568

Phosphoinositide 3-Kinases, Protein Kinase B, and Signalling through Insulin Receptor

References

 1. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231:232–235.

 2. Murray I. Paulescu and the isolation of insulin. J Hist Med. 1971;26:150– 157.

 3. Henderson JR. Who really discovered insulin? Guy’s Hospital Gazette 1971;85:314–318.

 4. Kasuga M, Karlsson FA, Kahn CR. Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science. 1982;215:185–187.

 5. von Mehring J, Minkowski O. Diabetes mellitus nach Pankreasexstirpation. Arch Exp Pathol Pharmakol. 1890;26:371–387.

 6. Gley E. Action des extraits de pancréas sclérosé sur des chiens diabétiqués (par extirpation du pancréas). C R Soc Biol (Paris). 1922;87:1322–1325.

 7. Freychet P. Pancreatic hormones. In: Baulieu E-E, Kelly PA, eds. Hormones: From Molecules to Disease. London: Chapman & Hall; 1990:490–532.

 8. Foster DW, McGarry JD. Glucose, lipid and protein metabolism. In: Griffin JE, Ojeda SR, eds. Textbook of Endocrine Physiology. New York: Oxford University Press; 2006:393–419.

569

Signal Transduction

  9. Chong LD, Traynor-Kaplan A, Bokoch GM, Schwartz MA. The small GTP-binding protein Rho regulates a phosphatidylinositol 4-phosphate 5-kinase in mammalian cells. Cell. 1994;79:507–513.

10.Tolias KF, Hartwig JH, Ishihara H, Shibasaki Y, Cantley LC, Carpenter CL. Type I phosphatidylinositol-4-phosphate 5-kinase mediates Racdependent actin assembly. Curr Biol. 2000;10:153–156.

11.Honda A, Nogami M, Yokozeki T, et al. Phosphatidylinositol 4-phosphate 5-kinase is a downstream effector of the small G protein ARF6 in membrane ruffle formation. Cell. 1999;99:521–532.

12.Traynor Kaplan AE, Harris AL, Thompson BL, Taylor P, Sklar LA. An inositol tetrakisphosphate-containing phospholipid in activated neutrophils. Nature. 1988;334:353–356.

13.Ireton K, Payrastre B, Chap H, et al. A role for phosphoinositide 3-kinase in bacterial invasion. Science. 1996;274:780–782.

14.Gary JD, Wurmser LS, Emr SD. Fap1p is essential for PtdIns(3)P 5- kinase activity and the maintenance of vacuolar size and membrane homeostasis. J Cell Biol. 1998;143:65–79.

15.Herman PK, Stack JH, DeModena JA, Emr SD. A novel protein kinase homolog essential for protein sorting to the yeast lysosome-like vacuole. Cell. 1991;64:425–437.

16.Walker EH, Perisic O, Ried C, Stephens L, Williams RL. Structural insights into phosphoinositide 3-kinase catalysis and signaling. Nature. 1999;402:313–320.

17.Yu J, Zhang Y, McIlroy J, Rordorf-Nikolic T, Orr GA, Backer JM. Regulation of the p85/p110 phosphatidylinositol 3 -kinase: stabilization and inhibition of the p110 catalytic subunit by the p85 regulatory subunit. Mol Cell Biol. 1998;18:1379–1387.

18.Rudd E, Schneider H. Lymphocyte signaling: Cbl sets the threshold for autoimmunity. Curr Biol. 2000;10:R344.

19.Musacchio A, Cantley LC, Harrison SC. Crystal structure of the breakpoint cluster region-homology domain from phosphoinositide 3-kinase p85 subunit. Proc Natl Acad Sci U S A. 1996;93:14373–14378.

20.Diekmann D, Brill S, Garrett MD, et al. Bcr encodes a GTPase-activating protein for p21rac. Nature. 1991;351:400–402.

21.Rodriguez-Viciana P, Warne PH, Dhand R, et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994;370:527–532.

22.Voigt P, Brock C, Nurnberg B, Schaefer M. Assigning functional domains within the p101 regulatory subunit of phosphoinositide 3-kinase . J Biol Chem. 2005;280:5121–5127.

23.Wymann MP, Pirola L, Pirola L. Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta. 1998;1436:127–150.

24.Van Haesebroeck B, Jones GE, Allen WE, et al. Distinct PI(3)Ks mediate mitogenic signalling and cell migration in macrophages. Nature Cell Biol. 1999;1:69–71.

570

Phosphoinositide 3-Kinases, Protein Kinase B, and Signalling through Insulin Receptor

25.Foster FM, Traer CJ, Abraham SM, Fry MJ. The phosphoinositide (PI) 3- kinase family. J Cell Sci. 2003;116:3037–3040.

26.Dann SG, Thomas G. The amino acid sensitive TOR pathway from yeast to mammals. FEBS Lett. 2006;580:2821–2829.

27.Gunther R, Abbas HK, Mirocha CJ. Acute pathological effects on rats of orally administered wortmannin-containing preparations and purified wortmannin from Fusarium oxysporum. Food Chem Toxicol. 1989;27:

173–179.

28.Closse A, Haefliger W, Hauser D, Gubler HU, Dewald B, Baggiolini M. 2,3-Dihydrobenzofuran-2-ones: a new class of highly potent antiinflammatory agents. J Med Chem. 1981;24:1465–1471.

29.Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, et al. Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol Cell Biol. 1996;16:1722– 1733.

30.Nakanishi S, Kakita S, Takahashi I, et al. Wortmannin a microbial product inhibitor of myosin light chain kinase, J Biol Chem. 1992;267:2157–2164.

31.Walker EH, Pacold ME, Perisic O, et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin myricetin, and staurosporine. Mol Cell. 2000;6:909–919.

32.Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378:785–789.

33.Guinebault C, Payrastre B, Racaud SC, et al. Integrin-dependent translocation of phosphoinositide 3-kinase to the cytoskeleton of thrombin-activated platelets involves specific interactions of p85 with actin filaments and focal adhesion kinase. J Cell Biol. 1995;129: 831–842.

34.Jones PF, Jakubowicz T, Pitossi FJ, Maurer F, Hemmings BA. Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily. Proc Natl Acad Sci USA. 1991;88:4171– 4175.

35.Frodin M, Antal TL, Dummler BA, et al. A phosphoserine/threoninebinding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation. EMBO J. 2002;21:5396–5407.

36.Bellacosa A, Testa JR, Staal SP, Tsichlis PN. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science. 1991;254:274–277.

37.Corvera S, Czech MP. Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction. Trends Neurosci. 1998;8:442–447.

38.Yang J, Cron P, Good VM, Thompson V, Hemmings BA, Barford D. Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nat Struct Biol. 2002;9:940–944.

571

Signal Transduction

39.Mora A, Komander D, van Aalten DM, Alessi DR. PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol. 2004;15:161–170.

40.Yang J, Cron P, Thompson V, Good VM, Hess D, Hemmings BA,

Barford D. Molecular mechanism for the regulation of protein kinase B/ Akt by hydrophobic motif phosphorylation. Mol Cell. 2002;9:1227–1240.

41.Davies TG, Verdonk ML, Graham B, et al. A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera. J Mol Biol. 2007;367:882–894.

42.McKern NM, Lawrence MC, Streltsov VA, et al. Structure of the insulin receptor ectodomain reveals a folded-over conformation. Nature. 2006;443:218–221.

43.White MF, Shoelson SE, Keutmann H, Kahn CR. A cascade of tyrosine autophosphorylation in the -subunit activates the phosphotransferase of the insulin receptor. J Biol Chem. 1988;263:2969–2980.

44.Valverde AM, Lorenzo M, Pons S, White MF, Benito M. Insulin receptor substrate (IRS) proteins IRS-1 and IRS-2 differential signaling in the insulin/insulin-like growth factor-I pathways in fetal brown adipocytes. Mol Endocrinol. 1998;12:688–697.

45.Franke TF, Yang SI, Chan TO, et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell. 1995;81:727–736.

46.Franke TF, Kaplan DR, Cantley LC, Toker A. Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science. 1997;275:665–668.

47.Jiang ZY, Zhou QL, Coleman KA, Chouinard M, Boese Q, Czech MP. Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing. Proc Natl Acad Sci U S A. 2003;100:7569– 7574.

48.Hu J. Liu.J, Ghirlando R, Saltiel AR, and Hubbard SR. Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor. Mol Cell. 2006;12:1379–1389.

49.Frame S, Cohen P, Biondi RM. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell. 2001;7:1321–1327.

50.Benomar Y, Naour N, Aubourg A, et al. Insulin and leptin induce Glut4 plasma membrane translocation and glucose uptake in a human neuronal cell line by a phosphatidylinositol 3-kinase- dependent mechanism. Endocrinology. 2006;147:2550–2556.

51.Wilson JC, Rochford JJ, Wolfrum C, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science. 2004;304:1325–1328.

52.Chang L, Chiang S, Saltiel AR. Insulin signaling and the regulation of glucose transport. Mol Med. 2006;10:65–71.

572

Phosphoinositide 3-Kinases, Protein Kinase B, and Signalling through Insulin Receptor

53.Novak-Hofer I, Thomas G. Epidermal growth factor-mediated activation of an S6 kinase in Swiss mouse 3T3 cells. J Biol Chem. 1985;260:10314– 10319.

54.Smith CJ, Rubin CS, Rosen OM. Insulin-treated 3T3-L1 adipocytes and cell-free extracts derived from them incorporate 32P into ribosomal protein S6. Proc Natl Acad Sci U S A. 1980;77:2641–2645.

55.Ruvinsky I, Meyuhas O. Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem Sci. 2006;31:342–348.

56.van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277:805–808.

57.The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993;75:1305–1315.

58.Bourneville DM. Sclérose tubéreuse des circonvolutions cérébrales. Arch Neurol (Paris). 1880;1:81–89.

59.Bourneville DM, Brissaud E. Encéphalite ou sclérose tubéreuse des circonvolutions cérébrales. Arch Neurol (Paris). 2008;1:390–410.

60.Cheadle JP, Reeve MP, Sampson JR, Kwiatkowski DJ. Molecular genetic advances in tuberous sclerosis. Hum Genet. 2000;107:97–114.

61.Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3- kinase/AKT pathway. Proc Natl Acad Sci U S A. 1999;96:4240–4245.

62.Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003;17:1829–1834.

63.Inoki K, Li Y, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signaling. Nat Cell Biol. 2002;4:648–657.

64.Dan HC, Sun M, Yang L, et al. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem. 2002;277:35364–35370.

65.Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev. 2001;15:807–826.

66.Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4EBP1. Proc Natl Acad Sci USA. 1998;95:1432–1437.

67.Holz MK, Ballif BA, Gygi SP, Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005;123: 569–580.

68.Yamamoto-Honda R, Tobe K, Kaburagi Y, et al. Upstream mechanisms of glycogen synthase activation by insulin and insulin-like growth factor-I. Glycogen synthase activation is antagonized by wortmannin or LY294002 but not by rapamycin or by inhibiting p21ras. J Biol Chem. 1995;270:2724–2729.

573

Signal Transduction

69.Dorrestijn J, Ouwens DM, Van den Berghe N, Bos JL, Maassen JA. Expression of a dominant-negative Ras mutant does not affect stimulation of glucose uptake and glycogen synthesis by insulin. Diabetologia. 1996:558–563.

70.Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell. 2005;121:179–193.

71.Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci U S A. 2004;101:13489–13494.

72.Rajasekhar VK, Viale A, Socci ND, Wiedmann M, Hu X, Holland EC. Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol Cell. 2003;122:889–901.

73.Martin DE, Hall MN. The expanding TOR signaling network. Curr Opin Cell Biol. 2005;17:158–166.

74.Shamji AF, Nghiem P, Schreiber SL. Integration of growth factor and nutrient signaling: implications for cancer biology. Mol Cell. 2003;12:271– 280.

75.Roccio M, Bos JL, Zwartkruis FJ. Regulation of the small GTPase Rheb by amino acids. Oncogene. 2006;25:657–664.

76.Alessi DR, Sakamoto K, Bayascas JR. LKB1-dependent signaling pathways. Annu Rev Biochem. 2006;75:137–163.

77.Baas AF, Kuipers J, van der Wel NN, et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell. 2004;116:457–466.

78.Samuels Y, Velculescu VE. Oncogenic mutations of PIK3CA in human cancers. Cell Cycle. 2004;3:1221–1224.

79.Leevers SJ, Weinkove D, MacDougall LK, Hafen E, Waterfield MD. The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J. 1996;15:6584–6594.

80.Goberdhan DC, Paricio N, Goodman EC, Mlodzik M, Wilson C. Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway. Genes Dev. 1999;13:3244–3258.

81.Verdu J, Buratovich MA, Wilder EL, Birnbaum MJ. Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nat Cell Biol. 1999;1:500–506.

82.Manning BD, Logsdon MN, Lipovsky AI, Abbott D, Kwiatkowski DJ, Cantley LC. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev. 2005;19:1773–1778.

83.Lazaris-Karatzas A, Montine KS, Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5 cap. Nature. 1990;345:544–547.

574

Phosphoinositide 3-Kinases, Protein Kinase B, and Signalling through Insulin Receptor

84.Fingar DC, Salama S, Tsou C, Harlow E, Blenis J, Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 202;16:1472–1487.

85.Leevers SJ, Weinkove D, MacDougall LK, Hafen E, Waterfield MD. The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J. 1996;15:6584–6594.

86.Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science. 1999;283:1544–1548.

87.Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399:601–605.

88.Kwiatkowska K, Sobotka A. Signaling pathways in phagocytosis. Bioessays. 1999;21:422–431.

89.Xu J, Wang F, Van Keymeulen A, et al. Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils. Cell. 2003;114:201–214.

90.Li Z, Hannigan M, Mo Z, et al. Directional sensing requires G -mediated PAK1 and PIX -dependent activation of Cdc42. Cell. 2003;114:215–227.

91.Kops GJ, de Ruiter ND, de Vries-Smits AM, Powell DR, Bos JL, Burgering BM. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature. 1999;398:630–634.

575