The phosphatidylinositol 3-Kinase–AKT pathway in human cancer (original) (raw)

• Whitman, M., Kaplan, D. R., Schaffhausen, B., Cantley, L. & Roberts, T. M. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 315, 239–242 (1985).
  Article CAS PubMed Google Scholar
• White, M. F. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol. Cell. Biochem. 182, 3–11 (1998).
  Article CAS PubMed Google Scholar
• Inukai, K. et al. p85α gene generates three isoforms of regulatory subunit for phosphatidylinositol 3-kinase p50α, p55α, and p85α, with different PI 3-kinase activity elevating responses to insulin. J. Biol. Chem. 272, 7873–7882 (1997).
  Article CAS PubMed Google Scholar
• Kaliman, P. et al. Insulin-like growth factors require phosphatidylinositol 3-kinase to signal myogenesis: dominant negative p85 expression blocks differentiation of L6E9 muscle cells. Mol. Endocrinol. 12, 66–77(1998).
  Article CAS PubMed Google Scholar
• Ueki, K., Algenstaedt, P., Mauvais-Jarvis, F. & Kahn, C. R. Positive and negative regulation of phosphoinositide 3-kinase-dependent signaling pathways by three different gene products of the p85 α regulatory subunit. Mol. Cell. Biol. 20, 8035–8046 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Yu, J. et al. Regulation of the p85/p110 phosphatidylinositol 3′-kinase: stabilization and inhibition of the p110α catalytic subunit by the p85 regulatory subunit. Mol. Cell. Biol. 18, 1379–1387 (1998).Shows that p85 can both extend the half-life of p110 and inhibit its activity. This inhibitory effect was relieved by the binding of phosphotyrosine peptides to the SH2 domain of p85.
  Article CAS PubMed PubMed Central Google Scholar
• Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527–532 (1994).Links RAS to the PI3K–AKT pathway.
  Article CAS PubMed Google Scholar
• Kodaki, T. et al. The activation of phosphatidylinositol 3-kinase by Ras. Curr. Biol. 4, 798–806 (1994).
  Article CAS PubMed Google Scholar
• Cuevas, B. D. et al. Tyrosine phosphorylation of p85 relieves its inhibitory activity on phosphatidylinositol 3-kinase. J. Biol. Chem. 276, 27455–27461 (2001).
  Article CAS PubMed Google Scholar
• Steck, P. A. et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nature Genet. 15, 356–362 (1997).
  Article CAS PubMed Google Scholar
• Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997).References 10 and 11 describe the molecular cloning of PTEN on the basis of breast cancer and glioma studies, respectively, and reports a high frequency of PTEN mutation by various cancer cell lines, xenografts and primary tumours.
  Article CAS PubMed Google Scholar
• Myers, M. P. et al. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc. Natl Acad. Sci. USA 95, 13513–13518 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Haas-Kogan, D. et al. Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr. Biol. 8, 1195–1198 (1998).
  Article CAS PubMed Google Scholar
• Stambolic, V. et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29–39 (1998).Shows that PTEN is a negative regulator of AKT and can reduce intracellular levels of PIP 3 and dephosphorylate PIP 3 in vitro.
  Article CAS PubMed Google Scholar
• Wu, X., Senechal, K., Neshat, M. S., Whang, Y. E. & Sawyers, C. L. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc. Natl Acad. Sci. USA 95, 15587–15591 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Maehama, T. & Dixon, J. E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 273, 13375–13378 (1998).The first report that PTEN has lipid phosphatase actitivty.
  Article CAS PubMed Google Scholar
• Gu, J. et al. Shc and FAK differentially regulate cell motility and directionality modulated by PTEN. J. Cell Biol. 146, 389–403 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Tamura, M. et al. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 280, 1614–1617 (1998).
  Article CAS PubMed Google Scholar
• Scheid, M. P. et al. Phosphatidylinositol(3,4,5)P3 is essential but not sufficient for PKB activation: phosphatidylinositol(3,4)P2 is required for PKB phosphorylation at Ser473. Studies using cells from _Ship_−/− knockout mice. J. Biol. Chem. 277, 9027 – 9035 (2002).
  Article CAS PubMed Google Scholar
• Helgason, C. D. et al. A dual role for Src homology 2 domain-containing inositol-5-phosphatase (SHIP) in immunity: aberrant development and enhanced function of B lymphocytes in SHIP−/− mice. J. Exp. Med. 191, 781–794 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, Q. et al. SHIP is a negative regulator of growth factor receptor-mediated PKB/AKT activation and myeloid cell survival. Genes Dev. 13, 786–791 (1999).Shows that Ship-deficient mice have hyperproliferation of myeloid cells, increased survival of neutrophils, and enhanced PIP 3 accumulation and Akt activation upon engagement of certain cytokine receptors.
  Article CAS PubMed PubMed Central Google Scholar
• Datta, S. R., Brunet, A. & Greenberg, M. E. Cellular survival: a play in three Akts. Genes Dev. 13, 2905–2927 (1999).
  Article CAS PubMed Google Scholar
• Scheid, M. P. & Woodgett, J. R. PKB/AKT: functional insights from genetic models. Nature Rev. Mol. Cell Biol. 2, 760–768 (2001).
  Article CAS Google Scholar
• Andjelkovic, M. et al. Role of translocation in the activation and function of protein kinase B. J. Biol. Chem. 272, 31515–31524 (1997).
  Article CAS PubMed Google Scholar
• Bellacosa, A. et al. Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 17, 313–325 (1998).
  Article CAS PubMed Google Scholar
• Vanhaesebroeck, B. & Alessi, D. R. The PI3K–PDK1 connection: more than just a road to PKB. Biochem. J. 346, 561–576 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Stokoe, D. et al. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 277, 567–570 (1997).Shows that PIP 3 is necessary for AKT recruitment to the membrane and phosphorylation of AKT on the PDK1 site (Thr308).
  Article CAS PubMed Google Scholar
• Alessi, D. R. et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase-Bα. Curr. Biol. 7, 261–269 (1997).
  Article CAS PubMed Google Scholar
• Toker, A. & Newton, A. C. Akt/protein kinase B is regulated by autophosphorylation at the hypothetical PDK-2 site. J. Biol. Chem. 275, 8271–8274 (2000).
  Article CAS PubMed Google Scholar
• Laine, J., Kunstle, G., Obata, T., Sha, M. & Noguchi, M. The protooncogene TCL1 is an Akt kinase coactivator. Mol. Cell 6, 395–407 (2000).
  Article CAS PubMed Google Scholar
• Andjelkovic, M. et al. Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC–PK/PKB) promoted by serum and protein phosphatase inhibitors. Proc. Natl Acad. Sci. USA 93, 5699–5704 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Maira, S. M. et al. Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science 294, 374–380 (2001).
  Article CAS PubMed Google Scholar
• Sato, S., Fujita, N. & Tsuruo, T. Modulation of Akt kinase activity by binding to Hsp90. Proc. Natl Acad. Sci. USA 97, 10832–10837 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Dudek, H. et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275, 661–665 (1997).
  Article CAS PubMed Google Scholar
• Li, J. et al. The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene. Cancer Res. 58, 5667–5672 (1998).
  CAS PubMed Google Scholar
• Datta, S. R. et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231–241 (1997).Shows that growth-factor-induced activation of AKT phosphorylates BAD and inhibits BAD-induced apoptosis in primary neurons.
  Article CAS PubMed Google Scholar
• Cardone, M. H. et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 282, 1318–1321 (1998).
  Article CAS PubMed Google Scholar
• Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999).
  Article CAS PubMed Google Scholar
• Romashkova, J. A. & Makarov, S. S. NF-κB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401, 86–90 (1999).Shows that PDGF stimulation of fibroblasts causes phosphorylation and activation of IKK by AKT and subsequent activation of NF-κB. This finding links the PI3K–AKT pathway to anti-apoptotic transcription.
  Article CAS PubMed Google Scholar
• Kane, L. P., Shapiro, V. S., Stokoe, D. & Weiss, A. Induction of NF-κB by the Akt/PKB kinase. Curr. Biol. 9, 601–604 (1999).
  Article CAS PubMed Google Scholar
• Mayo, L. D. & Donner, D. B. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl Acad. Sci. USA 98, 11598–11603 (2001).Shows that phosphorylation of MDM2 by AKT enhances its nuclear translocation, resulting in destabilization of the p53 protein.
  Article CAS PubMed PubMed Central Google Scholar
• Zhou, B. P. et al. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nature Cell Biol. 3, 973–982 (2001).
  Article CAS PubMed Google Scholar
• Stambolic, V. et al. Regulation of PTEN transcription by p53. Mol. Cell 8, 317–325 (2001).
  Article CAS PubMed Google Scholar
• Diehl, J. A., Cheng, M., Roussel, M. F. & Sherr, C. J. Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12, 3499–3511 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Graff, J. R. et al. Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J. Biol. Chem. 275, 24500–24505 (2000).
  Article CAS PubMed Google Scholar
• Dijkers, P. F. et al. Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol. Cell. Biol. 20, 9138–9148 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Medema, R. H., Kops, G. J., Bos, J. L. & Burgering, B. M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782–787 (2000).
  Article CAS PubMed Google Scholar
• Lawlor, M. A. & Rotwein, P. Insulin-like growth factor-mediated muscle cell survival: central roles for Akt and cyclin-dependent kinase inhibitor p21. Mol. Cell. Biol. 20, 8983–8995 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Rossig, L. et al. Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells. Mol. Cell. Biol. 21, 5644–5657 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Vemuri, G. S. & Rittenhouse, S. E. Wortmannin inhibits serum-induced activation of phosphoinositide 3-kinase and proliferation of CHRF-288 cells. Biochem. Biophys. Res. Commun. 202, 1619–1623 (1994).
  Article CAS PubMed Google Scholar
• Castoria, G. et al. PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. EMBO J. 20, 6050–6059 (2001).Shows that the induction of PI3K triggers oestrogen-dependent S-phase entry in breast cancer cells.
  Article CAS PubMed PubMed Central Google Scholar
• Schmelzle, T. & Hall, M. N. TOR, a central controller of cell growth. Cell 103, 253–262 (2000).
  Article CAS PubMed Google Scholar
• Nave, B. T., Ouwens, M., Withers, D. J., Alessi, D. R. & Shepherd, P. R. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem. J. 344, 427–431 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Brunn, G. J. et al. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J. 15, 5256–5267 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Bodine, S. C. et al. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nature Cell Biol. 3, 1014–1019 (2001).
  Article CAS PubMed Google Scholar
• Rommel, C. et al. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nature Cell Biol. 3, 1009–1013 (2001).
  Article CAS PubMed Google Scholar
• Dennis, P. B. et al. Mammalian TOR: a homeostatic ATP sensor. Science 294, 1102–1105 (2001).
  Article CAS PubMed Google Scholar
• Radimerski, T. et al. dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1. Nature Cell Biol. 4, 251–255 (2002).
  Article CAS PubMed Google Scholar
• Pullen, N. et al. Phosphorylation and activation of p70s6k by PDK1. Science 279, 707–710 (1998).
  Article CAS PubMed Google Scholar
• Liliental, J. et al. Genetic deletion of the Pten tumor suppressor gene promotes cell motility by activation of Rac1 and Cdc42 GTPases. Curr. Biol. 10, 401–404 (2000).
  Article CAS PubMed Google Scholar
• Jiang, K. et al. Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity in natural killer cells. Nature Immunol. 1, 419–425 (2000).
  Article CAS Google Scholar
• Welch, H., Eguinoa, A., Stephens, L. R. & Hawkins, P. T. Protein kinase B and Rac are activated in parallel within a phosphatidylinositide 3OH-kinase-controlled signaling pathway. J. Biol. Chem. 273, 11248–11256 (1998).
  Article CAS PubMed Google Scholar
• Han, J. et al. Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav. Science 279, 558–560 (1998).Shows that phosphorylation of the RAC-specific guanine nucleotide exchange factor (GEF) VAV1 is enhanced by PIP 3 and inhibited by PIP 2 . These findings link a GEF to PI3K-mediated RAC activation.
  Article CAS PubMed Google Scholar
• Welch, H. C. et al. P-Rex1, a PtdIns(3,4,5)P(3)- and Gβγ-regulated guanine-nucleotide exchange factor for Rac. Cell 108, 809–821 (2002).
  Article CAS PubMed Google Scholar
• Krugmann, S. et al. Identification of ARAP3, a novel PI3K effector regulating both Arf and Rho GTPases, by selective capture on phosphoinositide affinity matrices. Mol. Cell 9, 95–108 (2002).
  Article CAS PubMed Google Scholar
• Jimenez, C. et al. Role of the PI3K regulatory subunit in the control of actin organization and cell migration. J. Cell Biol. 151, 249–261 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Brunet, A. et al. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol. Cell. Biol. 21, 952–965 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Park, J. et al. Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J. 18, 3024–3033 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Stocker, H. et al. Living with lethal PIP3 levels: viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB. Science 295, 2088 –2091 (2002).Uses fly genetics to argue that Akt might be the sole effector of PIP 3 action.
  Article CAS PubMed Google Scholar
• Shayesteh, L. et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nature Genet. 21, 99–102 (1999).
  Article CAS PubMed Google Scholar
• Bellacosa, A. et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int. J. Cancer 64, 280–285 (1995).
  Article CAS PubMed Google Scholar
• Cheng, J. Q. et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc. Natl Acad. Sci. USA 93, 3636–3641 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Ruggeri, B. A., Huang, L., Wood, M., Cheng, J. Q. & Testa, J. R. Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol. Carcinog. 21, 81–86 (1998).
  Article CAS PubMed Google Scholar
• Philp, A. J. et al. The phosphatidylinositol 3′-kinase p85α gene is an oncogene in human ovarian and colon tumors. Cancer Res. 61, 7426–7429 (2001).
  CAS PubMed Google Scholar
• Jimenez, C. et al. Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. EMBO J. 17, 743–753 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Moscatello, D. K., Holgado-Madruga, M., Emlet, D. R., Montgomery, R. B. & Wong, A. J. Constitutive activation of phosphatidylinositol 3-kinase by a naturally occurring mutant epidermal growth factor receptor. J. Biol. Chem. 273, 200–206 (1998).
  Article CAS PubMed Google Scholar
• Watanabe, T. et al. A novel amplification at 17q21-23 in ovarian cancer cell lines detected by comparative genomic hybridization. Gynecol. Oncol. 81, 172–177 (2001).
  Article CAS PubMed Google Scholar
• Barlund, M. et al. Multiple genes at 17q23 undergo amplification and overexpression in breast cancer. Cancer Res. 60, 5340–5344 (2000).
  CAS PubMed Google Scholar
• Barlund, M. et al. Detecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarray analysis. J. Natl Cancer Inst. 92, 1252–1259 (2000).
  Article CAS PubMed Google Scholar
• Ali, I. U., Schriml, L. M. & Dean, M. Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J. Natl Cancer Inst. 91, 1922–1932 (1999).A thorough review of the frequency of PTEN mutation in various cancers.
  Article CAS PubMed Google Scholar
• Georgescu, M. M., Kirsch, K. H., Akagi, T., Shishido, T. & Hanafusa, H. The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region. Proc. Natl Acad. Sci. USA 96, 10182–10187 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Whang, Y. et al. Frequent transcriptional silencing of the tumor suppressor PTEN/MMAC1 gene in prostate cancer xenografts. Proc. Natl Acad. Sci. USA 95, 5246 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Pekarsky, Y. et al. Tcl1 enhances Akt kinase activity and mediates its nuclear translocation. Proc. Natl Acad. Sci. USA 97, 3028–3033 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Shioi, T. et al. The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J. 19, 2537–2548 (2000).Shows that cardiac-specific expression of constitutively active p110 causes an enlargement of the heart and that dominant-negative p110 causes a reduction in heart size.
  Article CAS PubMed PubMed Central Google Scholar
• Shioi, T. et al. Akt/protein kinase B promotes organ growth in transgenic mice. Mol. Cell. Biol. 22, 2799–2809 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Borlado, L. R. et al. Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo. FASEB J. 14, 895–903 (2000).
  Article CAS PubMed Google Scholar
• Jones, R. G. et al. Protein kinase B regulates T lymphocyte survival, nuclear factor κB activation, and Bcl-xL levels in vivo. J. Exp. Med. 191, 1721–1734 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Tuttle, R. L. et al. Regulation of pancreatic β-cell growth and survival by the serine/threonine protein kinase Akt1/PKBα. Nature Med. 7, 1133–1137 (2001).
  Article CAS PubMed Google Scholar
• Bernal-Mizrachi, E., Wen, W., Stahlhut, S., Welling, C. M. & Permutt, M. A. Islet β-cell expression of constitutively active Akt1/PKBα induces striking hypertrophy, hyperplasia, and hyperinsulinemia. J. Clin. Invest. 108, 1631–1638 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Hutchinson, J., Jin, J., Cardiff, R. D., Woodgett, J. R. & Muller, W. J. Activation of Akt (protein kinase B) in mammary epithelium provides a critical cell survival signal required for tumor progression. Mol. Cell. Biol. 21, 2203–2212 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Holland, E. C. et al. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genet. 25, 55–57 (2000).Shows that co-expression of activated Ras and Akt in neural progenitor cells in the mouse brain induces glioblastoma.
  Article CAS PubMed Google Scholar
• Stambolic, V. et al. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in Pten+/− mice. Cancer Res. 60, 3605–3611 (2000).
  CAS PubMed Google Scholar
• Suzuki, A. et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr. Biol. 8, 1169–1178 (1998).
  Article CAS PubMed Google Scholar
• Podsypanina, K. et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc. Natl Acad. Sci. USA 96, 1563–1568 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Di Cristofano, A., Pesce, B., Cordon-Cardo, C. & Pandolfi, P. P. Pten is essential for embryonic development and tumour suppression. Nature Genet. 19, 348–355 (1998).The first report of a Pten -knockout mouse phenotype. Homozygous deletion causes embryonic lethality, whereas heterozygous animals are viable but develop various tumors.
  Article CAS PubMed Google Scholar
• Goldman, J. M. & Melo, J. V. Targeting the BCR–ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1084–1086 (2001).
  Article CAS PubMed Google Scholar
• Druker, B. J. et al. Activity of a specific inhibitor of the BCR–ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med. 344, 1038–1042 (2001).
  Article CAS PubMed Google Scholar
• van Oosterom, A. T. et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358, 1421–1423 (2001).
  Article CAS PubMed Google Scholar
• Baselga, J. et al. in 2001 AACR-NCI–EORTC International Conference 128 (American Association for Cancer Research, Fontainebleau Hilton Hotel. Miami Beach, Florida, 2001).
  Google Scholar
• Hu, L., Hofmann, J., Lu, Y., Mills, G. B. & Jaffe, R. B. Inhibition of phosphatidylinositol 3′-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res. 62, 1087–1092 (2002).Shows that non-toxic doses of LY294002 can increase the efficacy of the chemotherapeutic paclitaxel in an ovarian cancer xenograft model.
  CAS PubMed Google Scholar
• Bi, L., Okabe, I., Bernard, D. J., Wynshaw-Boris, A. & Nussbaum, R. L. Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110α subunit of phosphoinositide 3-kinase. J. Biol. Chem. 274, 10963–10968 (1999).Describes the phenotype of the p110α-targeted deletion.
  Article CAS PubMed Google Scholar
• Tybulewicz, V. L., Crawford, C. E., Jackson, P. K., Bronson, R. T. & Mulligan, R. C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-Abl proto-oncogene. Cell 65, 1153–1163 (1991).
  Article CAS PubMed Google Scholar
• Reith, A. D. et al. W mutant mice with mild or severe developmental defects contain distinct point mutations in the kinase domain of the c-Kit receptor. Genes Dev. 4, 390–400 (1990).
  Article CAS PubMed Google Scholar
• Soriano, P. The PDGFα receptor is required for neural crest cell development and for normal patterning of the somites. Development 124, 2691–2700 (1997).
  Article CAS PubMed Google Scholar
• Neshat, M. S. et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98, 10314–10319 (2001).Shows that loss of PTEN or stable expression of constitutively active AKT sensitizes tumours to inhibition of mTOR.
  Article CAS PubMed PubMed Central Google Scholar
• Podsypanina, K. et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice. Proc. Natl Acad. Sci. USA 98, 10320–10325 (2001).Shows that pre-neoplastic uterine lesions fail to develop or regress in Pten +/− mice that are treated with an inhibitor of mTor.
  Article CAS PubMed PubMed Central Google Scholar
• Guba, M. et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Med. 8, 128–135 (2002).
  Article CAS PubMed Google Scholar
• Chan, J. et al. Dissection of angiogenic signaling in zebrafish using a chemical genetic approach. Cancer Cell 1, 257–267 (2002).
  Article CAS PubMed Google Scholar
• Mayo, L. D., Dixon, J. E., Durden, D. L., Tonks, N. K. & Donner, D. B. PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J. Biol. Chem. 277, 5484–5489 (2002).
  Article CAS PubMed Google Scholar
• Li, D. M. & Sun, H. PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc. Natl Acad. Sci. USA 95, 15406–15411 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Heymont, J. et al. TEP1, the yeast homolog of the human tumor suppressor gene PTEN/MMAC1/TEP1, is linked to the phosphatidylinositol pathway and plays a role in the developmental process of sporulation. Proc. Natl Acad. Sci. USA 97, 12672–12677 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Casamayor, A., Torrance, P. D., Kobayashi, T., Thorner, J. & Alessi, D. R. Functional counterparts of mammalian protein kinases PDK1 and SGK in budding yeast. Curr. Biol. 9, 186–197 (1999).
  Article CAS PubMed Google Scholar
• Cardenas, M. E., Cutler, N. S., Lorenz, M. C., Di Como, C. J. & Heitman, J. The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev. 13, 3271–3279 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Fabrizio, P., Pozza, F., Pletcher, S. D., Gendron, C. M. & Longo, V. D. Regulation of longevity and stress resistance by Sch9 in yeast. Science 292, 288–290 (2001).
  Article CAS PubMed Google Scholar
• Morris, J. Z., Tissenbaum, H. A. & Ruvkun, G. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382, 536–539 (1996).Shows that mutations in Age1 , the C. elegans Pi3k homologue, causes dauer formation and an extension of lifespan.
  Article CAS PubMed Google Scholar
• Kimura, K. D., Tissenbaum, H. A., Liu, Y. & Ruvkun, G. daf2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277, 942–946 (1997).
  Article CAS PubMed Google Scholar
• Paradis, S., Ailion, M., Toker, A., Thomas, J. H. & Ruvkun, G. A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Genes Dev. 13, 1438–1452 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Lin, K., Hsin, H., Libina, N. & Kenyon, C. Regulation of the Caenorhabditis elegans longevity protein DAF16 by insulin/IGF1 and germline signaling. Nature Genet. 28, 139–145 (2001).
  Article CAS PubMed Google Scholar
• Mihaylova, V. T., Borland, C. Z., Manjarrez, L., Stern, M. J. & Sun, H. The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway. Proc. Natl Acad. Sci. USA 96, 7427–7432 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Verdu, J., Buratovich, M. A., Wilder, E. L. & Birnbaum, M. J. Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nature Cell Biol. 1, 500–506 (1999).
  Article CAS PubMed Google Scholar
• Zhang, H., Stallock, J. P., Ng, J. C., Reinhard, C. & Neufeld, T. P. Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev. 14, 2712–2724 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Montagne, J. et al. Drosophila S6 kinase: a regulator of cell size. Science 285, 2126–2129 (1999).
  Article CAS PubMed Google Scholar
• Miron, M. et al. The translational inhibitor 4E-BP is an effector of PI(3)K/Akt signalling and cell growth in Drosophila. Nature Cell Biol. 3, 596–601 (2001).
  Article CAS PubMed Google Scholar
• Goberdhan, D. C., Paricio, N., Goodman, E. C., Mlodzik, M. & Wilson, C. Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway. Genes Dev. 13, 3244–3258 (1999).Shows that in Drosophila , Pten is a negative regulator of Pi3k and mutations in Pten result in increased cell size and cell number.
  Article CAS PubMed PubMed Central Google Scholar
• Gao, X., Neufeld, T. P. & Pan, D. Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and-independent pathways. Dev. Biol. 221, 404–418 (2000).
  Article CAS PubMed Google Scholar
• Sasaki, T. et al. Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)Kγ. Nature 406, 897–902 (2000).
  Article CAS PubMed Google Scholar
• Barbier, M. et al. Tumour biology. Weakening link to colorectal cancer? Nature 413, 796 (2001).
  Article CAS PubMed Google Scholar
• Fruman, D. A. et al. Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85α. Nature Genet. 26, 379–382 (2000).Shows that targeted deletion of all isoforms of Pi3k regulatory subunits results in lethality, unlike deletions of individual isoforms.
  Article CAS PubMed Google Scholar
• Suzuki, H. et al. Xid-like immunodeficiency in mice with disruption of the p85α subunit of phosphoinositide 3-kinase. Science 283, 390–392 (1999).
  Article CAS PubMed Google Scholar
• Cho, H., Thorvaldsen, J. L., Chu, Q., Feng, F. & Birnbaum, M. J. Akt1/PKBα is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J. Biol. Chem. 276, 38349–38352 (2001).
  Article CAS PubMed Google Scholar
• Chen, W. S. et al. Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev. 15, 2203–2208 (2001).Shows that Akt1 -deficient mice are smaller than wild-type littermates, have a shorter lifespan after exposure to genotoxic stress and show more susceptibility to apoptosis in the testes and thymus.
  Article CAS PubMed PubMed Central Google Scholar
• Cho, H. et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ). Science 292, 1728–1731 (2001).
  Article CAS PubMed Google Scholar
• Wang, S. I. et al. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 57, 4183–4186 (1997).
  CAS PubMed Google Scholar
• Saito, M. et al. Allelic imbalance and mutations of the PTEN gene in ovarian cancer. Int. J. Cancer 85, 160–165 (2000).
  Article CAS PubMed Google Scholar
• Sun, M. et al. AKT1/PKBα kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am. J. Pathol. 159, 431–437 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Teng, D. H. et al. MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res. 57, 5221–5225 (1997).
  CAS PubMed Google Scholar
• Sun, M. et al. Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor-α (ERα) via interaction between ERα and PI3K. Cancer Res. 61, 5985–5991 (2001).
  CAS PubMed Google Scholar
• Yokoyama, Y. et al. Expression of PTEN and PTEN pseudogene in endometrial carcinoma. Int. J. Mol. Med. 6, 47–50 (2000).
  CAS PubMed Google Scholar
• Salvesen, H. B. et al. PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma. Int. J. Cancer 91, 22–26 (2001).
  Article CAS PubMed Google Scholar
• Kawamura, N. et al. PTEN/MMAC1 mutations in hepatocellular carcinomas: somatic inactivation of both alleles in tumors. Jpn. J. Cancer Res. 90, 413–418 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Celebi, J. T., Shendrik, I., Silvers, D. N. & Peacocke, M. Identification of PTEN mutations in metastatic melanoma specimens. J. Med. Genet. 37, 653–657 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Zhou, X. P. et al. Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. Am. J. Pathol. 157, 1123–1128 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Chang, J. G. et al. Mutation analysis of the PTEN/MMAC1 gene in cancers of the digestive tract. Eur. J. Cancer 35, 647–651 (1999).
  Article CAS PubMed Google Scholar
• Forgacs, E. et al. Mutation analysis of the PTEN/MMAC1 gene in lung cancer. Oncogene 17, 1557–1565 (1998).
  Article CAS PubMed Google Scholar
• Alimov, A. et al. Somatic mutation and homozygous deletion of PTEN/MMAC1 gene of 10q23 in renal cell carcinoma. Anticancer Res. 19, 3841–3846 (1999).
  CAS PubMed Google Scholar
• Dahia, P. L. et al. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res. 57, 4710–4713 (1997).
  CAS PubMed Google Scholar
• Halachmi, N. et al. Somatic mutations of the PTEN tumor suppressor gene in sporadic follicular thyroid tumors. Genes Chromosom. Cancer 23, 239–243 (1998).
  Article CAS PubMed Google Scholar
• Hsieh, M. C. et al. Mutation analysis of PTEN/MMAC1 in sporadic thyroid tumors. Kaohsiung J. Med. Sci. 16, 9–12 (2000).
  CAS PubMed Google Scholar
• Ringel, M. D. et al. Overexpression and overactivation of Akt in thyroid carcinoma. Cancer Res. 61, 6105–6111 (2001).
  CAS PubMed Google Scholar
• Nakahara, Y. et al. Mutational analysis of the PTEN/MMAC1 gene in non-Hodgkin's lymphoma. Leukemia 12, 1277–1280 (1998).
  Article CAS PubMed Google Scholar
• Sakai, A., Thieblemont, C., Wellmann, A., Jaffe, E. S. & Raffeld, M. PTEN gene alterations in lymphoid neoplasms. Blood 92, 3410–3415 (1998).
  Article CAS PubMed Google Scholar
• Fruman, D. A. et al. Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85α. Science 283, 393–397 (1999).
  Article CAS PubMed Google Scholar
• Terauchi, Y. et al. Increased insulin sensitivity and hypoglycaemia in mice lacking the p85α subunit of phosphoinositide 3-kinase. Nature Genet. 21, 230–235 (1999).
  Article CAS PubMed Google Scholar
• Hirsch, E. et al. Central role for G protein-coupled phosphoinositide 3-kinase-γ in inflammation. Science 287, 1049–1053 (2000).
  Article CAS PubMed Google Scholar
• Li, Z. et al. Roles of PLC-β2 and -β3 and PI3Kγ in chemoattractant-mediated signal transduction. Science 287, 1046–1049 (2000).
  Article CAS PubMed Google Scholar
• Sasaki, T. et al. Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 287, 1040–1046 (2000).
  Article CAS PubMed Google Scholar