Phosphatidylinositol 3-kinase: The oncoprotein

Current Topics in Microbiology and Immunology

Volumn 347, Issue 1, 2010, Pages 79-104

  Vogt, Peter K ^a   Hart, Jonathan R ^a   Gymnopoulos, Marco ^a   Jiang, Hao ^a   Kang, Sohye ^b   Bader, Andreas G ^c   Zhao, Li ^a   Denley, Adam ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

^b AMGEN INC   (United States)

^c SYNLOGIC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ISOENZYME; MUTANT PROTEIN; ONCOPROTEIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE ALPHA; PHOSPHATIDYLINOSITOL 3 KINASE DELTA; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE; PROTEIN KINASE B; PROTEIN P110; PROTEIN P85; PROTEIN TORC1; PROTEIN TORC2; PROTEIN TYROSINE KINASE; RAPTOR PROTEIN; RAS PROTEIN; TARGET OF RAPAMYCIN KINASE; UNCLASSIFIED DRUG;

ARTICLE; CARCINOGENESIS; CARCINOGENICITY; CATALYSIS; CYTOLOGY; ENZYME ACTIVITY; ENZYME SPECIFICITY; GENE; GENE MUTATION; HUMAN; MALIGNANT NEOPLASTIC DISEASE; MALIGNANT TRANSFORMATION; MOLECULAR BIOLOGY; MOLECULAR GENETICS; MUTATIONAL ANALYSIS; NONHUMAN; PIK3CA GENE; PIK3R1 GENE; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; SIGNAL TRANSDUCTION; WILD TYPE; ANIMAL; CELL TRANSFORMATION; GENETICS; MUTATION; NEOPLASM; PHYSIOLOGY; REVIEW;

RAPTORES;

ANIMALS; CELL TRANSFORMATION, NEOPLASTIC; HUMANS; ISOENZYMES; MUTATION; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES;

EID: 79952109377     PISSN: 0070217X     EISSN: None     Source Type: Book Series    
DOI: 10.1007/82-2010-80     Document Type: Article

References (181)

1. Abraham RT (2004) PI 3-kinase related kinases: 'big' players in stress-induced signaling pathways. DNA Repair (Amst) 3:883-887 (Pubitemid 38997930)
2. Ahmed NN, Franke TF, Bellacosa A, Datta K, Gonzalez-Portal ME, Taguchi T, Testa JR, Tsichlis PN (1993) The proteins encoded by c-akt and v-akt differ in post-translational modification, subcellular localization and oncogenic potential. Oncogene 8:1957-1963 (Pubitemid 23212429)
3. Alcazar I, Marques M, Kumar A, Hirsch E, Wymann M, Carrera AC, Barber DF (2007) Phosphoinositide 3-kinase gamma participates in T cell receptor-induced T cell activation. J Exp Med 204:2977-2987 (Pubitemid 350179565)
4. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA (1996a) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15: 6541-6551 (Pubitemid 26413787)
5. Alessi DR, Caudwell FB, Andjelkovic M, Hemmings BA, Cohen P (1996b) Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase. FEBS Lett 399:333-338 (Pubitemid 26426877)
6. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7:261-269 (Pubitemid 27176852)
7. Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, Kuehn N, Gray A, Giddings J, Peskett E, Fox R, Bruce I, Walker C, Sawyer C, Okkenhaug K, Finan P, Vanhaesebroeck B (2004) Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature 431:1007-1011 (Pubitemid 39434424)
8. Ali K, Camps M, Pearce WP, Ji H, Rückle T, Kuehn N, Pasquali C, Chabert C, Rommel C, Vanhaesebroeck B (2008) Isoform-specific functions of phosphoinositide 3-kinases: p110 delta but not p110 gamma promotes optimal allergic responses in vivo. J Immunol 180:2538-2544
9. Al-Saleem T, Wessner LL, Scheithauer BW, Patterson K, Roach ES, Dreyer SJ, Fujikawa K, Bjornsson J, Bernstein J, Henske EP (1998) Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer 83:2208-2216 (Pubitemid 28525404)
10. Amzel LM, Huang CH, Mandelker D, Lengauer C, Gabelli SB, Vogelstein B (2008) Structural comparisons of class I phosphoinositide 3-kinases. Nat Rev Cancer 8:665-669
11. Aoki M, Batista O, Bellacosa A, Tsichlis P, Vogt PK (1998) The akt kinase: molecular determinants of oncogenicity. Proc Natl Acad Sci USA 95:14950-14955 (Pubitemid 29003737)
12. Aoki M, Schetter C, Himly M, Batista O, Chang HW, Vogt PK (2000) The catalytic subunit of phosphoinositide 3-kinase: requirements for oncogenicity. J Biol Chem 275:6267-6275 (Pubitemid 30129917)
13. Aoki M, Blazek E, Vogt P (2001) A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc Natl Acad Sci USA 98:136-141 (Pubitemid 32095876)
14. Bader AG, Vogt PK (2005) Inhibition of protein synthesis by Y box-binding protein 1 blocks oncogenic cell transformation. Mol Cell Biol 25:2095-2106 (Pubitemid 40354610)
15. Bader AG, Vogt P (2008) Phosphorylation by Akt disables the anti-oncogenic activity of YB-1. Oncogene 27:1179-1182 (Pubitemid 351253182)
16. Bader AG, Felts KA, Jiang N, Chang HW, Vogt PK (2003) Y box-binding protein 1 induces resistance to oncogenic transformation by the phosphatidylinositol 3-kinase pathway. Proc Natl Acad Sci USA 100:12384-12389 (Pubitemid 37271569)
17. Bader AG, Kang S, Vogt PK (2006) Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci USA 103:1475-1479 (Pubitemid 43191190)
18. Bai D, Ueno L, Vogt PK (2009) Akt-mediated regulation of NFkB and the essentialness of NFkB for the oncogenicity of PI3K and Akt. Int J Cancer 125:2863-2870
19. Bénistant C, Chapuis H, Roche S (2000) A specific function for phosphatidylinositol 3-kinase alpha (p85alpha-p110alpha) in cell survival and for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in de novo DNA synthesis of human colon carcinoma cells. Oncogene 19:5083-5090
20. Bi L, Okabe I, Bernard DJ, Wynshaw-Boris A, Nussbaum RL (1999) Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase. J Biol Chem 274:10963-10968
21. Bi L, Okabe I, Bernard DJ, Nussbaum RL (2002) Early embryonic lethality in mice deficient in the p110beta catalytic subunit of PI 3-kinase. Mamm Genome 13:169-172 (Pubitemid 34185317)
22. Bondeva T, Pirola L, Bulgarelli-Leva G, Rubio I, Wetzker R, Wymann MP (1998) Bifurcation of lipid and protein kinase signals of PI3Kgamma to the protein kinases PKB and MAPK. Science 282:293-296 (Pubitemid 28487201)
23. Brachmann S, Fritsch C, Maira SM, Garcia-Echeverria C (2009) PI3K and mTOR inhibitors: a new generation of targeted anticancer agents. Curr Opin Cell Biol 21:194-198
24. Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061-1068
25. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655-1657 (Pubitemid 34579158)
26. Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS, Cantley LC (1990) Purification and characterization of phosphoinositide 3-kinase from rat liver. J Biol Chem 265:19704-19711 (Pubitemid 120013919)
27. Carson JD, Van Aller G, Lehr R, Sinnamon RH, Kirkpatrick RB, Auger KR, Dhanak D, Copeland RA, Gontarek RR, Tummino PJ, Luo L (2008) Effects of oncogenic p110alpha subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase. Biochem J 409:519-524 (Pubitemid 351184970)
28. Castro AF, Rebhun JF, Clark GJ, Quilliam LA (2003) Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin-and farnesylation-dependent manner. J Biol Chem 278:32493-32496 (Pubitemid 37055685)
29. Chang HW, Aoki M, Fruman D, Auger KR, Bellacosa A, Tsichlis PN, Cantley LC, Roberts TM, Vogt PK (1997) Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science 276:1848-1850 (Pubitemid 27443659)
30. Chaussade C, Cho K, Mawson C, Rewcastle GW, Shepherd PR (2009) Functional differences between two classes of oncogenic mutation in the PIK3CA gene. Biochem Biophys Res Commun 381:577-581
31. Cheng CK, Fan QW, Weiss WA (2009) PI3K signaling in glioma-animal models and therapeutic challenges. Brain Pathol 19:112-120
32. Ciraolo E, Iezzi M, Marone R, Marengo S, Curcio C, Costa C, Azzolino O, Gonella C, Rubinetto C, Wu H, Dastrú W, Martin EL, Silengo L, Altruda F, Turco E, Lanzetti L, Musiani P, Rückle T, Rommel C, Backer JM, Forni G, Wymann MP, Hirsch E (2008) Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development. Sci Signal 1:ra3
33. Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, Humphries LA, Rawlings D, Reynolds H, Vigorito E, Turner M (2002) A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med 196:753-763
34. Courtneidge SA, Smith AE (1984) The complex of polyoma virus middle-T antigen and pp 60csrc. EMBO J 3:585-591
35. Cuevas BD, Lu Y, Mao M, Zhang J, LaPushin R, Siminovitch K, Mills GB (2001) Tyrosine phosphorylation of p85 relieves its inhibitory activity on phosphatidylinositol 3-kinase. J Biol Chem 276:27455-27461
36. Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KL (2005) eIF4E promotes nuclear export of cyclin D1 mRNAs via an element in the 3'UTR. J Cell Biol 169:245-256 (Pubitemid 40656563)
37. Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KL (2006) eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol 175:415-426 (Pubitemid 44708066)
38. Currie R, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J (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):575-583
39. Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, Pledger WJ, Cheng JQ (2002) Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 277:35364-35370
40. Deane JA, Fruman DA (2004) Phosphoinositide 3-kinase: diverse roles in immune cell activation. Annu Rev Immunol 22:563-598 (Pubitemid 38680434)
41. Denley A, Kang S, Karst U, Vogt P (2008) Oncogenic signaling of class I PI3K isoforms. Oncogene 27:2561-2574 (Pubitemid 351550883)
42. Denley A, Gymnopoulos M, Kang S, Mitchell C, Vogt PK (2009) Requirement of phosphatidylinositol( 3, 4, 5)trisphosphate in phosphatidylinositol 3-kinase-induced oncogenic transformation. Mol Cancer Res 7:1132-1138
43. Dhand R, Hiles I, Panayotou G, Roche S, Fry MJ, Gout I, Totty NF, Truong O, Vicendo P, Yonezawa K et al (1994) PI 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity. EMBO J 13:522-533 (Pubitemid 24050666)
44. Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100:387-390
45. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606-619 (Pubitemid 44100518)
46. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, Chirieac LR, Kaur R, Lightbown A, Simendinger J, Li T, Padera RF, García-Echeverría C, Weissleder R, Mahmood U, Cantley L, Wong KK (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351-1356
47. Evdokimova V, Ovchinnikov LP, Sorensen PH (2006a) Y-box binding protein 1: providing a new angle on translational regulation. Cell Cycle 5:1143-1147 (Pubitemid 43845371)
48. Evdokimova V, Ruzanov P, Anglesio MS, Sorokin A, Ovchinnikov L, Buckley J, Triche TJ, Sonenberg N, Sorensen P (2006b) Akt-mediated YB-1 phosphorylation activates translation of silent mRNA species. Mol Cell Biol 26:277-292
49. Evdokimova V, Tognon C, Ng T, Ruzanov P, Melnyk N, Fink D, Sorokin A, Ovchinnikov LP, Davicioni E, Triche TJ, Sorensen PH (2009) Translational activation of snail1 and other developmentally regulated transcription factors by YB-1 promotes an epithelial-mesenchymal transition. Cancer Cell 15:402-415
50. Everitt JI, Goldsworthy TL, Wolf DC, Walker CL (1992) Hereditary renal cell carcinoma in the Eker rat: a rodent familial cancer syndrome. J Urol 148:1932-1936
51. Fan QW, Weiss WA (2006) Isoform specific inhibitors of PI3 kinase in glioma. Cell Cycle 5:2301-2305 (Pubitemid 44785836)
52. Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, Shokat KM, Weiss WA (2006) A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9:341-349 (Pubitemid 43668732)
53. Fan QW, Cheng CK, Nicolaides TP, Hackett CS, Knight ZA, Shokat KM, Weiss WA (2007) A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res 67:7960-7965 (Pubitemid 47395125)
54. Fan QW, Cheng C, Knight ZA, Haas-Kogan D, Stokoe D, James CD, McCormick F, Shokat KM, Weiss WA (2009) EGFR Signals to mTOR Through PKC and Independently of Akt in Glioma. Science Signal 2:ra4
55. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM (2009) Activesite inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7:e38
56. Filippa N, Sable CL, Hemmings BA, Van Obberghen E (2000) Effect of phosphoinositidedependent kinase 1 on protein kinase B translocation and its subsequent activation. Mol Cell Biol 20:5712-5721 (Pubitemid 30482904)
57. Foukas LC, Beeton CA, Jensen J, Phillips WA, Shepherd PR (2004) Regulation of phosphoinositide 3-kinase by its intrinsic serine kinase activity in vivo. Mol Cell Biol 24:966-975 (Pubitemid 38112162)
58. Fruman DA, Bismuth G (2009) Fine tuning the immune response with PI3K. Immunol Rev 228:253-272
59. Fruman DA, Meyers RE, Cantley L (1998) Phosphoinositide kinases. Annu Rev Biochem 67:481-507 (Pubitemid 28411136)
60. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G (2003) Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 11:1457-1466 (Pubitemid 36776533)
61. Garcia-Echeverria C, Sellers WR (2008) Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27:5511-5526
62. García-Martínez JM, Moran J, Clarke RG, Gray A, Cosulich SC, Chresta CM, Alessi DR (2009) Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J 421:29-42
63. Geering B, Cutillas PR, Nock G, Gharbi SI, Vanhaesebroeck B (2007) Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers. Proc Natl Acad Sci USA 104:7809-7814 (Pubitemid 47185833)
64. Ghigo A, Hirsch E (2008) Isoform selective phosphoinositide 3-kinase gamma and delta inhibitors and their therapeutic potential. Recent Pat Inflamm Allergy Drug Discov 2:1-10 (Pubitemid 351524318)
65. Graupera M, Guillermet-Guibert J, Foukas LC, Phng LK, Cain RJ, Salpekar A, Pearce W, Meek S, Millan J, Cutillas PR, Smith AJ, Ridley AJ, Ruhrberg C, Gerhardt H, Vanhaesebroeck B (2008) Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature 453:662-666 (Pubitemid 351769296)
66. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9-22 (Pubitemid 47001784)
67. Guertin DA, Sabatini DM (2009) The pharmacology of mTOR inhibition. Science Signal 2:pe24
68. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11:859-871 (Pubitemid 44804279)
69. Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, Meek S, Smith AJ, Okkenhaug K, Vanhaesebroeck B (2008) The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proc Natl Acad Sci USA 105:8292-8297 (Pubitemid 351904749)
70. Gymnopoulos M, Elsliger MA, Vogt PK (2007) Rare cancer-specific mutations in PIK3CA show gain of function. Proc Natl Acad Sci USA 104:5569-5574 (Pubitemid 47175721)
71. Hawkins PT, Anderson KE, Davidson K, Stephens LR (2006) Signalling through Class I PI3Ks in mammalian cells. Biochem Soc Trans 34:647-662 (Pubitemid 44796393)
72. He X, Zhu Z, Johnson C, Stoops J, Eaker A, Bowen W, Defrances M (2008) PIK3IP1, a negative regulator of PI3K, suppresses the development of hepatocellular carcinoma. Cancer Res 68:5591-5598
73. Hickey FB, Cotter TG (2006) BCR-ABL regulates phosphatidylinositol 3-kinase-p110gamma transcription and activation and is required for proliferation and drug resistance. J Biol Chem 281:2441-2450 (Pubitemid 43845703)
74. Hirsch E, Katanaev VL, Garlanda C, Azzolino O, Pirola L, Silengo L, Sozzani S, Mantovani A, Altruda F, Wymann MP (2000) Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science 287:1049-1053
75. Huang J, Manning BD (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 37:217-222
76. Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW, Vogelstein B, Gabelli SB, Amzel LM (2007) The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318:1744-1748 (Pubitemid 350274378)
77. Huang CH, Mandelker D, Gabelli SB, Amzel LM (2008) Insights into the oncogenic effects of PIK3CA mutations from the structure of p110alpha/p85alpha. Cell Cycle 7:1151-1156 (Pubitemid 351749265)
78. Huang J, Wu S, Wu CL, Manning BD (2009) Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. Cancer Res 69:6107-6114
79. Ikenoue T, Kanai F, Hikiba Y, Obata T, Tanaka Y, Imamura J, Ohta M, Jazag A, Guleng B, Tateishi K, Asaoka Y, Matsumura M, Kawabe T, Omata M (2005) Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 65:4562-4567 (Pubitemid 40740791)
80. Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648-657 (Pubitemid 34993700)
81. Inoki K, Li Y, Xu T, Guan KL (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17:1829-1834 (Pubitemid 36944560)
82. Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, Cantley LC, Brugge JS (2005) Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res 65:10992-11000 (Pubitemid 41713369)
83. Izumi H, Imamura T, Nagatani G, Ise T, Murakami T, Uramoto H, Torigoe T, Ishiguchi H, Yoshida Y, Nomoto M, Okamoto T, Uchiumi T, Kuwano M, Funa K, Kohno K (2001) Y boxbinding protein-1 binds preferentially to single-stranded nucleic acids and exhibits 30-> 50 exonuclease activity. Nucleic Acids Res 29:1200-1207 (Pubitemid 32186206)
84. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6:1122-1128 (Pubitemid 39468014)
85. Jaiswal BS, Janakiraman V, Kljavin NM, Chaudhuri S, Stern HM, Wang W, Kan Z, Dbouk HA, Peters BA, Waring P, Dela Vega T, Kenski DM, Bowman KK, Lorenzo M, Li H, Wu J, Modrusan Z, Stinson J, Eby M, Yue P, Kaminker JS, de Sauvage FJ, Backer JM, Seshagiri S (2009a) Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. Cancer Cell 16:463-474
86. Jaiswal BS, Janakiraman V, Kljavin NM, Eastham-Anderson J, Cupp JE, Liang Y, Davis DP, Hoeflich KP, Seshagiri S (2009b) Combined targeting of BRAF and CRAF or BRAF and PI3K effector pathways is required for efficacy in NRAS mutant tumors. PLoS ONE 4:e5717
87. Ji H, Rintelen F, Waltzinger C, Bertschy Meier D, Bilancio A, Pearce W, Hirsch E, Wymann MP, Rückle T, Camps M, Vanhaesebroeck B, Okkenhaug K, Rommel C (2007) Inactivation of PI3Kgamma and PI3Kdelta distorts T-cell development and causes multiple organ inflammation. Blood 110:2940-2947 (Pubitemid 350006947)
88. Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, Zhang J, Signoretti S, Loda M, Roberts TM, Zhao JJ (2008) Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454:776-779
89. Jiang H, Vogt PK (2008) Constitutively active Rheb induces oncogenic transformation. Oncogene 27:5729-5740
90. Jiang B, Zheng JZ, Aoki M, Vogt PK (2000) Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc Natl Acad Sci USA 97:1749-1753 (Pubitemid 30118514)
91. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P,Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801-1806
92. Jou ST, Carpino N, Takahashi Y, Piekorz R, Chao JR, Carpino N, Wang D, Ihle JN (2002) Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol 22:8580-8591 (Pubitemid 35397173)
93. Kang S, Bader AG, Vogt PK (2005) Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 102:802-807 (Pubitemid 40282746)
94. Kang S, Denley A, Vanhaesebroeck B, Vogt PK (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 (Pubitemid 43191158)
95. Kaplan DR, Pallas DC, Morgan W, Schaffhausen B, Roberts TM (1989) Mechanisms of transformation by polyoma virus middle T antigen. Biochim Biophys Acta 948:345-364
96. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110:163-175 (Pubitemid 34876545)
97. Klippel A, Kavanaugh WM, Pot D, Williams LT (1997) A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. Mol Cell Biol 17:338-344 (Pubitemid 26425623)
98. Knobbe CB, Trampe-Kieslich A, Reifenberger G (2005) Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas. Neuropathol Appl Neurobiol 31:486-490 (Pubitemid 41337782)
99. Kobayashi T, Minowa O, Kuno J, Mitani H, Hino O, Noda T (1999) Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. Cancer Res 59:1206-1211 (Pubitemid 29136248)
100. Kong D, Yamori T (2008) Phosphatidylinositol 3-kinase inhibitors: promising drug candidates for cancer therapy. Cancer Sci 99:1734-1740
101. Kwiatkowski DJ, Manning BD (2005) Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum Mol Genet 14 Spec No. 2:R251-R258 (Pubitemid 41631882)
102. Kwiatkowski DJ, Zhang H, Bandura JL, Heiberger KM, Glogauer M, el-Hashemite N, Onda H (2002) A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet 11:525-534 (Pubitemid 34257489)
103. Laffargue M, Calvez R, Finan P, Trifilieff A, Barbier M, Altruda F, Hirsch E, Wymann MP (2002) Phosphoinositide 3-kinase gamma is an essential amplifier of mast cell function. Immunity 16:441-451 (Pubitemid 34260921)
104. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943-1947 (Pubitemid 27148818)
105. Liu Z, Roberts TM (2006) Human tumor mutants in the p110alpha subunit of PI3K. Cell Cycle 5:675-677
106. Low S, Vougioukas VI, Hielscher T, Schmidt U, Unterberg A, Halatsch ME (2008) Pathogenetic pathways leading to glioblastoma multiforme: association between gene expressions and resistance to erlotinib. Anticancer Res 28:3729-3732
107. MacDonald GH, Itoh-Lindstrom Y, Ting JP (1995) The transcriptional regulatory protein, YB-1, promotes single-stranded regions in the DRA promoter. J Biol Chem 270:3527-3533
108. Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3, 4, 5-trisphosphate. J Biol Chem 273: 13375-13378 (Pubitemid 28268370)
109. Maira S, Voliva C, García-Echeverría C (2008) Class IA phosphatidylinositol 3-kinase: from their biologic implication in human cancers to drug discovery. Expert Opin Ther Targets 12:223-238 (Pubitemid 351284964)
110. Malagu K, Duggan H, Menear K, Hummersone M, Gomez S, Bailey C, Edwards P, Drzewiecki J, Leroux F, Quesada MJ, Hermann G, Maine S, Molyneaux CA, Le Gall A, Pullen J, Hickson I, Smith L, Maguire S, Martin N, Smith G, Pass M (2009) The discovery and optimisation of pyrido[2,3-d]pyrimidine-2,4-diamines as potent and selective inhibitors of mTOR kinase. Bioorg Med Chem Lett 19:5950-5953
111. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC (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 10:151-162 (Pubitemid 34876569)
112. Marcotte L, Crino PB (2006) The neurobiology of the tuberous sclerosis complex. Neuromolecular Med 8:531-546 (Pubitemid 44547518)
113. Marone R, Cmiljanovic V, Giese B, Wymann MP (2008) Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim Biophys Acta 1784:159-185
114. McManus EJ, Collins BJ, Ashby PR, Prescott AR, Murray-Tait V, Armit LJ, Arthur JS, Alessi DR (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 (Pubitemid 38737734)
115. Memmott RM, Dennis PA (2009) Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal 21:656-664
116. Mertens PR, Harendza S, Pollock AS, Lovett DH (1997) Glomerular mesangial cell-specific transactivation of matrix metalloproteinase 2 transcription is mediated by YB-1. J Biol Chem 272:22905-22912 (Pubitemid 27386113)
117. Milburn CC, Deak M, Kelly SM, Price NC, Alessi DR, van Aalten DM (2003) Binding of phosphatidylinositol 3, 4, 5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change. Biochem J 375:531-538 (Pubitemid 37433501)
118. Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, Schneidman-Duhovny D, Wolfson HJ, Backer JM, Williams RL (2007) Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317:239-242 (Pubitemid 47076198)
119. Mizoguchi M, Nutt CL, Mohapatra G, Louis DN (2004) Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas. Brain Pathol 14:372-377 (Pubitemid 39524966)
120. Nelander S, Wang W, Nilsson B, She QB, Pratilas C, Rosen N, Gennemark P, Sander C (2008) Models from experiments: combinatorial drug perturbations of cancer cells. Mol Syst Biol 4:216
121. Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H, Sawyers CL (2001) Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/ mTOR. Proc Natl Acad Sci USA 98:10314-10319 (Pubitemid 32803017)
122. Nicholson KM, Anderson NG (2002) The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14:381-395 (Pubitemid 34214843)
123. Nowak P, Cole DC, Brooijmans N, Bursavich MG, Curran KJ, Ellingboe JW, Gibbons JJ, Hollander I, Hu Y, Kaplan J, Malwitz DJ, Toral-Barza L, Verheijen JC, Zask A, Zhang WG, Yu K (2009) Discovery of potent and selective inhibitors of the mammalian target of rapamycin (mTOR) kinase. J Med Chem 52:7081-7089
124. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD, Smith AJ, Vanhaesebroeck B (2002) Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297:1031-1034 (Pubitemid 34856039)
125. Okkenhaug K, Bilancio A, Emery JL, Vanhaesebroeck B (2004) Phosphoinositide 3-kinase in T cell activation and survival. Biochem Soc Trans 32:332-335 (Pubitemid 38582121)
126. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82-85
127. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr., Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807-1812
128. Patton DT, Garçon F, Okkenhaug K (2007) The PI3K p110delta controls T-cell development, differentiation and regulation. Biochem Soc Trans 35:167-171 (Pubitemid 46596459)
129. Pirola L, Zvelebil MJ, Bulgarelli-Leva G, Van Obberghen E, Waterfield MD, Wymann MP (2001) Activation loop sequences confer substrate specificity to phosphoinositide 3-kinase alpha (PI3Kalpha). Functions of lipid kinase-deficient PI3Kalpha in signaling. J Biol Chem 276:21544-21554
130. Podsypanina K, Lee RT, Politis C, Hennessy I, Crane A, Puc J, Neshat M, Wang H, Yang L, Gibbons J, Frost P, Dreisbach V, Blenis J, Gaciong Z, Fisher P, Sawyers C, Hedrick-Ellenson L, Parsons R (2001) An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/-mice. Proc Natl Acad Sci USA 98:10320-10325 (Pubitemid 32803018)
131. Roche S, Downward J, Raynal P, Courtneidge SA (1998) A function for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in fibroblasts during mitogenesis: requirement for insulinand lysophosphatidic acid-mediated signal transduction. Mol Cell Biol 18:7119-7129 (Pubitemid 28533031)
132. Rodriguez-Borlado L, Barber DF, Hernandez C, Rodriguez-Marcos MA, Sanchez A, Hirsch E, Wymann M, Martinez AC, Carrera AC (2003) Phosphatidylinositol 3-kinase regulates the CD4/CD8 T cell differentiation ratio. J Immunol 170:4475-4482 (Pubitemid 36519952)
133. Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J (1996) Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation. EMBO J 15:2442-2451 (Pubitemid 26151184)
134. Sakurai H, Chiba H, Miyoshi H, Sugita T, Toriumi W (1999) IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain. J Biol Chem 274: 30353-30356
135. Samuels Y, Velculescu VE (2004) Oncogenic mutations of PIK3CA in human cancers. Cell Cycle 3:1221-1224 (Pubitemid 40268595)
136. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554 (Pubitemid 38541907)
137. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320:1496-1501 (Pubitemid 351929429)
138. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296-1302 (Pubitemid 38991819)
139. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/ PKB by the rictor-mTOR complex. Science 307:1098-1101 (Pubitemid 40262113)
140. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159-168
141. Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B, Wakeham A, Itie A, Bouchard D, Kozieradzki I, Joza N, Mak TW, Ohashi PS, Suzuki A, Penninger JM (2000) Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science 287:1040-1046
142. Schaffhausen BS, Roberts TM (2009) Lessons from polyoma middle T antigen on signaling and transformation: a DNA tumor virus contribution to the war on cancer. Virology 384:304-316
143. Shekar SC, Wu H, Fu Z, Yip SC, Nagajyothi CSM, Girvin ME, Backer JM (2005) Mechanism of constitutive phosphoinositide 3-kinase activation by oncogenic mutants of the p85 regulatory subunit. J Biol Chem 280:27850-27855 (Pubitemid 41076901)
144. Stephens L, Hawkins PT, Eguinoa A, Cooke F (1996) A heterotrimeric GTPase-regulated isoform of PI3K and the regulation of its potential effectors. Philos Trans R Soc Lond B Biol Sci 351:211-215 (Pubitemid 126745331)
145. Stephens LR, Eguinoa A, Erdjument-Bromage H, Lui M, Cooke F, Coadwell J, Smrcka AS, Thelen M, Cadwallader K, Tempst P, Hawkins PT (1997) The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell 89:105-114 (Pubitemid 27180590)
146. Stephens L, Williams R, Hawkins P (2005) Phosphoinositide 3-kinases as drug targets in cancer. Curr Opin Pharmacol 5:357-365 (Pubitemid 40932037)
147. Stoyanov B, Volinia S, Hanck T, Rubio I, Loubtchenkov M, Malek D, Stoyanova S, Vanhaesebroeck B, Dhand R, Nürnberg B (1995) Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science 269:690-693
148. Sugimoto Y, Whitman M, Cantley L, Erikson RL (1984) Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. Proc Natl Acad Sci USA 81:2117-2121 (Pubitemid 14146614)
149. Sugita H, Dan S, Kong D, Tomida A, Yamori T (2008) A new evaluation method for quantifying PI3K activity by HTRF assay. Biochem Biophys Res Commun 377:941-945
150. Sujobert P, Bardet V, Cornillet-Lefebvre P, Hayflick JS, Prie N, Verdier F, Vanhaesebroeck B, Muller O, Pesce F, Ifrah N, Hunault-Berger M, Berthou C, Villemagne B, Jourdan E, Audhuy B, Solary E, Witz B, Harousseau JL, Himberlin C, Lamy T, Lioure B, Cahn JY, Dreyfus F, Mayeux P, Lacombe C, Bouscary D (2005) Essential role for the p110delta isoformin phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 106:1063-1066 (Pubitemid 41076455)
151. Sutherland BW, Kucab J, Wu J, Lee C, Cheang MC, Yorida E, Turbin D, Dedhar S, Nelson C, Pollak M, Leighton Grimes H, Miller K, Badve S, Huntsman D, Blake-Gilks C, Chen M, Pallen CJ, Dunn SE (2005) Akt phosphorylates the Y-box binding protein 1 at Ser102 located in the cold shock domain and affects the anchorage-independent growth of breast cancer cells. Oncogene 24:4281-4292 (Pubitemid 40961781)
152. Svitkin YV, Evdokimova VM, Brasey A, Pestova TV, Fantus D, Yanagiya A, Imataka H, Skabkin MA, Ovchinnikov LP, Merrick WC, Sonenberg N (2009) General RNA-binding proteins have a function in poly(A)-binding protein-dependent translation. EMBO J 28:58-68
153. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 13:1259-1268 (Pubitemid 36953298)
154. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284:8023-8032
155. Torbett NE, Luna-Moran A, Knight ZA, Houk A, Moasser M, Weiss W, Shokat KM, Stokoe D (2008) A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. Biochem J 415:97-110
156. Utermark T, Schaffhausen BS, Roberts TM, Zhao JJ (2007) The p110alpha isoform of phosphatidylinositol 3-kinase is essential for polyomavirus middle T antigen-mediated transformation. J Virol 81:7069-7076 (Pubitemid 46986643)
157. Vanhaesebroeck B, Alessi DR (2000) The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 346(pt 3):561-576 (Pubitemid 30171014)
158. Vanhaesebroeck B, Waterfield MD (1999) Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res 253:239-254
159. Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD (1997) Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 22:267-272 (Pubitemid 27310948)
160. Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ, Waterfield MD (2001) Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 70:535-602 (Pubitemid 32662219)
161. Vanhaesebroeck B, Ali K, Bilancio A, Geering B, Foukas LC (2005) Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem Sci 30:194-204 (Pubitemid 40463309)
162. Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ, Hennessy BT, Tseng H, Pochanard P, Kim SY, Dunn IF, Schinzel AC, Sandy P, Hoersch S, Sheng Q, Gupta PB, Boehm JS, Reiling JH, Silver S, Lu Y, Stemke-Hale K, Dutta B, Joy C, Sahin AA, Gonzalez-Angulo AM, Lluch A, Rameh LE, Jacks T, Root DE, Lander ES, Mills GB, Hahn WC, Sellers WR, Garraway LA (2009) AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16:21-32
163. Walker EH, Perisic O, Ried C, Stephens L, Williams RL (1999) Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 402:313-320 (Pubitemid 129516270)
164. Wee S, Wiederschain D, Maira SM, Loo A, Miller C, deBeaumont R, Stegmeier F, Yao YM, Lengauer C (2008) PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci USA 105:13057-13062
165. Whitman M, Kaplan DR, Schaffhausen B, Cantley L, Roberts TM (1985) Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 315:239-242 (Pubitemid 15064453)
166. Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B (2007) The genomic landscapes of human breast and colorectal cancers. Science 318:1108-1113 (Pubitemid 350134889)
167. Wu H, Shekar SC, Flinn RJ, El-Sibai M, Jaiswal BS, Sen KI, Janakiraman V, Seshagiri S, Gerfen GJ, Girvin ME, Backer JM (2009) Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110alpha and are disrupted in oncogenic p85 mutants. Proc Natl Acad Sci USA. 106:20258-20263
168. Wymann MP, Schneiter R (2008) Lipid signalling in disease. Nat Rev Mol Cell Biol 9:162-176 (Pubitemid 351158917)
169. Yap T, Garrett M, Walton M, Raynaud F, Debono J, Workman P (2008) Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol 8:393-412
170. Yart A, Chap H, Raynal P (2002) Phosphoinositide 3-kinases in lysophosphatidic acid signaling: regulation and cross-talk with the Ras/mitogen-activated protein kinase pathway. Biochim Biophys Acta 1582:107-111 (Pubitemid 34634118)
171. Yu K, Toral-Barza L, Shi C, Zhang WG, Lucas J, Shor B, Kim J, Verheijen J, Curran K, Malwitz DJ, Cole DC, Ellingboe J, Ayral-Kaloustian S, Mansour TS, Gibbons JJ, Abraham RT, Nowak P, Zask A (2009) Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 69:6232-6240
172. Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27:5497-5510
173. Zasedateleva OA, Krylov AS, Prokopenko DV, Skabkin MA, Ovchinnikov LP, Kolchinsky A, Mirzabekov AD (2002) Specificity of mammalian Y-box binding protein p50 in interaction with ss and ds DNA analyzed with generic oligonucleotide microchip. J Mol Biol 324:73-87 (Pubitemid 35352181)
174. Zask A, Verheijen JC, Curran K, Kaplan J, Richard DJ, Nowak P, Malwitz DJ, Brooijmans N, Bard J, Svenson K, Lucas J, Toral-Barza L, Zhang WG, Hollander I, Gibbons JJ, Abraham RT, Ayral-Kaloustian S, Mansour TS, Yu K (2009) ATP-Competitive Inhibitors of the Mammalian Target of Rapamycin: Design and Synthesis of Highly Potent and Selective Pyrazolopyrimidines. J Med Chem 52:5013-5016
175. Zhang H, Cicchetti G, Onda H, Koon HB, Asrican K, Bajraszewski N, Vazquez F, Carpenter CL, Kwiatkowski DJ (2003a) Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J Clin Invest 112:1223-1233 (Pubitemid 38056299)
176. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D (2003b) Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 5:578-581 (Pubitemid 36781094)
177. Zhang H, Liu G, Dziubinski M, Yang Z, Ethier SP, Wu G (2008) Comprehensive analysis of oncogenic effects of PIK3CA mutations in human mammary epithelial cells. Breast Cancer Res Treat 112:217-227
178. Zhao JJ, Roberts TM (2006) PI3 kinases in cancer: from oncogene artifact to leading cancer target. Sci STKE 2006:pe52
179. Zhao L, Vogt P (2008a) Class I PI3K in oncogenic cellular transformation. Oncogene 27: 5486-5496
180. Zhao L, Vogt PK (2008b) Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci USA 105:2652-2657 (Pubitemid 351520568)
181. Zhao JJ, Liu Z, Wang L, Shin E, Loda MF, Roberts TM (2005) The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl Acad Sci USA 102:18443-18448 (Pubitemid 43011245)