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Phosphatidylinositol 3-Kinase: The Oncoprotein

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Book cover Phosphoinositide 3-kinase in Health and Disease

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 347))

Abstract

The catalytic and regulatory subunits of class I phosphoinositide 3-kinase (PI3K) have oncogenic potential. The catalytic subunit p110α and the regulatory subunit p85 undergo cancer-specific gain-of-function mutations that lead to enhanced enzymatic activity, ability to signal constitutively, and oncogenicity. The β, γ, and δ isoforms of p110 are cell-transforming as overexpressed wild-type proteins. Class I PI3Ks have the unique ability to generate phosphoinositide 3,4,5 trisphosphate (PIP3). Class II and class III PI3Ks lack this ability. Genetic and cell biological evidence suggests that PIP3 is essential for PI3K-mediated oncogenicity, explaining why class II and class III enzymes have not been linked to cancer. Mutational analysis reveals the existence of at least two distinct molecular mechanisms for the gain of function seen with cancer-specific mutations in p110α; one causing independence from upstream receptor tyrosine kinases, the other inducing independence from Ras. An essential component of the oncogenic signal that is initiated by PI3K is the TOR (target of rapamycin) kinase. TOR is an integrator of growth and of metabolic inputs. In complex with the raptor protein (TORC1), it controls cap-dependent translation, and this function is essential for PI3K-initiated oncogenesis.

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References

  • Abraham RT (2004) PI 3-kinase related kinases: ‘big’ players in stress-induced signaling pathways. DNA Repair (Amst) 3:883–887

    Article  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Bader AG, Vogt P (2008) Phosphorylation by Akt disables the anti-oncogenic activity of YB-1. Oncogene 27:1179–1182

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Bader AG, Kang S, Vogt PK (2006) Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci USA 103:1475–1479

    Article  PubMed  CAS  Google Scholar 

  • Bai D, Ueno L, Vogt PK (2009) Akt-mediated regulation of NFκB and the essentialness of NFκB for the oncogenicity of PI3K and Akt. Int J Cancer 125:2863–2870

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

    Article  CAS  Google Scholar 

  • Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Cheng CK, Fan QW, Weiss WA (2009) PI3K signaling in glioma–animal models and therapeutic challenges. Brain Pathol 19:112–120

    Article  PubMed  CAS  Google Scholar 

  • Ciraolo E, Iezzi M, Marone R, Marengo S, Curcio C, Costa C, Azzolino O, Gonella C, Rubinetto C, Wu H, Dastrù 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Courtneidge SA, Smith AE (1984) The complex of polyoma virus middle-T antigen and pp 60c-src. EMBO J 3:585–591

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Deane JA, Fruman DA (2004) Phosphoinositide 3-kinase: diverse roles in immune cell activation. Annu Rev Immunol 22:563–598

    Article  PubMed  CAS  Google Scholar 

  • Denley A, Kang S, Karst U, Vogt P (2008) Oncogenic signaling of class I PI3K isoforms. Oncogene 27:2561–2574

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100:387–390

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Evdokimova V, Ovchinnikov LP, Sorensen PH (2006a) Y-box binding protein 1: providing a new angle on translational regulation. Cell Cycle 5:1143–1147

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Fan QW, Weiss WA (2006) Isoform specific inhibitors of PI3 kinase in glioma. Cell Cycle 5:2301–2305

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7:e38

    Google Scholar 

  • Filippa N, Sable CL, Hemmings BA, Van Obberghen E (2000) Effect of phosphoinositide-dependent kinase 1 on protein kinase B translocation and its subsequent activation. Mol Cell Biol 20:5712–5721

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Fruman DA, Bismuth G (2009) Fine tuning the immune response with PI3K. Immunol Rev 228:253–272

    Article  PubMed  CAS  Google Scholar 

  • Fruman DA, Meyers RE, Cantley L (1998) Phosphoinositide kinases. Annu Rev Biochem 67:481–507

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Echeverria C, Sellers WR (2008) Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27:5511–5526

    Article  PubMed  CAS  Google Scholar 

  • GarcÚa-MartÚnez 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

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22

    Article  PubMed  CAS  Google Scholar 

  • Guertin DA, Sabatini DM (2009) The pharmacology of mTOR inhibition. Science Signal 2:pe24

    Article  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Hawkins PT, Anderson KE, Davidson K, Stephens LR (2006) Signalling through Class I PI3Ks in mammalian cells. Biochem Soc Trans 34:647–662

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Huang J, Manning BD (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 37:217–222

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 box-binding protein-1 binds preferentially to single-stranded nucleic acids and exhibits 3′– > 5′ exonuclease activity. Nucleic Acids Res 29:1200–1207

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Jiang H, Vogt PK (2008) Constitutively active Rheb induces oncogenic transformation. Oncogene 27:5729–5740

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Kong D, Yamori T (2008) Phosphatidylinositol 3-kinase inhibitors: promising drug candidates for cancer therapy. Cancer Sci 99:1734–1740

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Liu Z, Roberts TM (2006) Human tumor mutants in the p110alpha subunit of PI3K. Cell Cycle 5:675–677

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Marcotte L, Crino PB (2006) The neurobiology of the tuberous sclerosis complex. Neuromolecular Med 8:531–546

    Article  PubMed  CAS  Google Scholar 

  • Marone R, Cmiljanovic V, Giese B, Wymann MP (2008) Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim Biophys Acta 1784:159–185

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Memmott RM, Dennis PA (2009) Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal 21:656–664

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Nicholson KM, Anderson NG (2002) The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14:381–395

    Article  PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Okkenhaug K, Bilancio A, Emery JL, Vanhaesebroeck B (2004) Phosphoinositide 3-kinase in T cell activation and survival. Biochem Soc Trans 32:332–335

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Patton DT, Garçon F, Okkenhaug K (2007) The PI3K p110delta controls T-cell development, differentiation and regulation. Biochem Soc Trans 35:167–171

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Roche S, Downward J, Raynal P, Courtneidge SA (1998) A function for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in fibroblasts during mitogenesis: requirement for insulin- and lysophosphatidic acid-mediated signal transduction. Mol Cell Biol 18:7119–7129

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Stephens L, Williams R, Hawkins P (2005) Phosphoinositide 3-kinases as drug targets in cancer. Curr Opin Pharmacol 5:357–365

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 106:1063–1066

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Vanhaesebroeck B, Alessi DR (2000) The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 346(pt 3):561–576

    Article  PubMed  CAS  Google Scholar 

  • Vanhaesebroeck B, Waterfield MD (1999) Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res 253:239–254

    Article  PubMed  CAS  Google Scholar 

  • Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD (1997) Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 22:267–272

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • Wymann MP, Schneiter R (2008) Lipid signalling in disease. Nat Rev Mol Cell Biol 9:162–176

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27:5497–5510

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Zhao JJ, Roberts TM (2006) PI3 kinases in cancer: from oncogene artifact to leading cancer target. Sci STKE 2006:pe52

    Article  PubMed  Google Scholar 

  • Zhao L, Vogt P (2008a) Class I PI3K in oncogenic cellular transformation. Oncogene 27:5486–5496

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

Work of the authors is supported by grants from the National Cancer Institute. This is manuscript number 20111 of The Scripps Research Institute.

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  1. Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Peter K. Vogt, Jonathan R. Hart, Marco Gymnopoulos, Hao Jiang, Li Zhao & Adam Denley

  2. Amgen, One Amgen Center Drive, Thousand Oaks, CA, 91320, USA

    Sohye Kang

  3. Mirna Therapeutics Inc., 2150 Woodward, Suite 100, Austin, TX, 78744, USA

    Andreas G. Bader

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    Christian Rommel

  2. , Institute of Cancer and the London Schoo, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom

    Bart Vanhaesebroeck

  3. , Dept. Molecular & Exp. Medicine, Scripps Research Institute, N. Torrey Pines Road 10550, La Jolla, 92037, California, USA

    Peter K. Vogt

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Vogt, P.K. et al. (2010). Phosphatidylinositol 3-Kinase: The Oncoprotein. In: Rommel, C., Vanhaesebroeck, B., Vogt, P. (eds) Phosphoinositide 3-kinase in Health and Disease. Current Topics in Microbiology and Immunology, vol 347. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_80

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