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[해외논문] Targeting the phosphoinositide 3-kinase pathway in cancer 원문보기

Nature reviews. Drug discovery, v.8 no.8, 2009년, pp.627 - 644  

Liu, Pixu (Departments of Cancer Biology, Dana–) ,  Cheng, Hailing (Farber Cancer Institute, Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.) ,  Roberts, Thomas M. (Departments of Cancer Biology, Dana–) ,  Zhao, Jean J. (Farber Cancer Institute, Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.)

Abstract AI-Helper 아이콘AI-Helper

The phosphoinositide 3-kinase (PI3K) pathway is a key signal transduction system that links oncogenes and multiple receptor classes to many essential cellular functions, and is perhaps the most commonly activated signalling pathway in human cancer. This pathway therefore presents both an opportunity...

참고문헌 (203)

  1. Nature Rev. Cancer I Vivanco 2 489 2002 10.1038/nrc839 Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nature Rev. Cancer 2, 489-501 (2002). 

  2. Nature Rev. Cancer AG Bader 5 921 2005 10.1038/nrc1753 Bader, A. G., Kang, S., Zhao, L. & Vogt, P. K. Oncogenic PI3K deregulates transcription and translation. Nature Rev. Cancer 5, 921-929 (2005). 

  3. Nature Rev. Genet. JA Engelman 7 606 2006 10.1038/nrg1879 Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nature Rev. Genet. 7, 606-619 (2006). A recent comprehensive review on PI3K. 

  4. Nature Rev. Cancer M Cully 6 184 2006 10.1038/nrc1819 Cully, M., You, H., Levine, A. J. & Mak, T. W. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nature Rev. Cancer 6, 184-192 (2006). 

  5. Proc. Natl Acad. Sci. USA LC Cantley 96 4240 1999 10.1073/pnas.96.8.4240 Cantley, L. C. & Neel, B. G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc. Natl Acad. Sci. USA 96, 4240-4245 (1999). 

  6. Nature Rev. Drug Discov. BT Hennessy 4 988 2005 10.1038/nrd1902 Hennessy, B. T., Smith, D. L., Ram, P. T., Lu, Y. & Mills, G. B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nature Rev. Drug Discov. 4, 988-1004 (2005). 

  7. Annu. Rev. Biochem. DA Fruman 67 481 1998 10.1146/annurev.biochem.67.1.481 Fruman, D. A., Meyers, R. E. & Cantley, L. C. Phosphoinositide kinases. Annu. Rev. Biochem. 67, 481-507 (1998). 

  8. Annu. Rev. Cell Dev. Biol. R Katso 17 615 2001 10.1146/annurev.cellbio.17.1.615 Katso, R. et al. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 17, 615-675 (2001). 

  9. J. Biol. Chem. P Voigt 281 9977 2006 10.1074/jbc.M512502200 Voigt, P., Dorner, M. B. & Schaefer, M. Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase gamma that is highly expressed in heart and interacts with PDE3B. J. Biol. Chem. 281, 9977-9986 (2006). 

  10. Curr. Biol. S Suire 15 566 2005 10.1016/j.cub.2005.02.020 Suire, S. et al. p84, a new Gβγ-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110γ. Curr. Biol. 15, 566-570 (2005). 

  11. Proc. Natl Acad. Sci. USA JD Chang 104 8077 2007 10.1073/pnas.0702663104 Chang, J. D. et al. Deletion of the phosphoinositide 3-kinase p110γ gene attenuates murine atherosclerosis. Proc. Natl Acad. Sci. USA 104, 8077-8082 (2007). 

  12. Cell E Patrucco 118 375 2004 10.1016/j.cell.2004.07.017 Patrucco, E. et al. PI3Kγ modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 118, 375-387 (2004). 

  13. Science T Sasaki 287 1040 2000 10.1126/science.287.5455.1040 Sasaki, T. et al. Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 287, 1040-1046 (2000). 

  14. Biochem. J. JM Backer 410 1 2008 10.1042/BJ20071427 Backer, J. M. The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem. J. 410, 1-17 (2008). 

  15. Nature Rev. Mol. Cell Biol. MP Scheid 2 760 2001 10.1038/35096067 Scheid, M. P. & Woodgett, J. R. PKB/AKT: functional insights from genetic models. Nature Rev. Mol. Cell Biol. 2, 760-768 (2001). 

  16. Curr. Biol. DR Alessi 7 776 1997 10.1016/S0960-9822(06)00336-8 Alessi, D. R. et al. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr. Biol. 7, 776-789 (1997). 

  17. Science L Stephens 279 710 1998 10.1126/science.279.5351.710 Stephens, L. et al. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 279, 710-714 (1998). 

  18. Science DD Sarbassov 307 1098 2005 10.1126/science.1106148 Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098-1101 (2005). 

  19. Cell BD Manning 129 1261 2007 10.1016/j.cell.2007.06.009 Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129, 1261-1274 (2007). 

  20. Cell S Wullschleger 124 471 2006 10.1016/j.cell.2006.01.016 Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471-484 (2006). 

  21. Nature Rev. Cancer DM Sabatini 6 729 2006 10.1038/nrc1974 Sabatini, D. M. mTOR and cancer: insights into a complex relationship. Nature Rev. Cancer 6, 729-734 (2006). 

  22. Nature Cell Biol. K Inoki 4 648 2002 10.1038/ncb839 Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biol. 4, 648-657 (2002). 

  23. Mol. Cell BD Manning 10 151 2002 10.1016/S1097-2765(02)00568-3 Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C. 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 (2002). 

  24. Nature Cell Biol. E Vander Haar 9 316 2007 10.1038/ncb1547 Vander Haar, E., Lee, S. I., Bandhakavi, S., Griffin, T. J. & Kim, D. H. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nature Cell Biol. 9, 316-323 (2007). 

  25. N. Engl. J. Med. PB Crino 355 1345 2006 10.1056/NEJMra055323 Crino, P. B., Nathanson, K. L. & Henske, E. P. The tuberous sclerosis complex. N. Engl. J. Med. 355, 1345-1356 (2006). 

  26. Genes Dev. N Hay 18 1926 2004 10.1101/gad.1212704 Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 18, 1926-1945 (2004). 

  27. Sci. STKE JJ Zhao 2006 pe52 2006 Zhao, J. J. & Roberts, T. M. PI3 kinases in cancer: from oncogene artifact to leading cancer target. Sci. STKE 2006, pe52 (2006). 

  28. Science LD Wood 318 1108 2007 10.1126/science.1145720 Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108-1113 (2007). 

  29. Nature Genet. RK Thomas 39 347 2007 10.1038/ng1975 Thomas, R. K. et al. High-throughput oncogene mutation profiling in human cancer. Nature Genet. 39, 347-351 (2007). 

  30. 10.1038/nature07385 Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061-1068 (2008). 

  31. Science DW Parsons 321 1807 2008 10.1126/science.1164382 Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807-1812 (2008). 

  32. Science Y Samuels 304 554 2004 10.1126/science.1096502 Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004). This study showed that PIK3CA is frequently mutated in human cancer. 

  33. Nature L Ding 455 1069 2008 10.1038/nature07423 Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069-1075 (2008). 

  34. J. Clin. Oncol. I Sansal 22 2954 2004 10.1200/JCO.2004.02.141 Sansal, I. & Sellers, W. R. The biology and clinical relevance of the PTEN tumor suppressor pathway. J. Clin. Oncol. 22, 2954-2963 (2004). 

  35. Nature Genet. PA Steck 15 356 1997 10.1038/ng0497-356 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). 

  36. Cell L Salmena 133 403 2008 10.1016/j.cell.2008.04.013 Salmena, L., Carracedo, A. & Pandolfi, P. P. Tenets of PTEN tumor suppression. Cell 133, 403-414 (2008). 

  37. Semin. Cell Dev. Biol. R Parsons 15 171 2004 10.1016/j.semcdb.2003.12.021 Parsons, R. Human cancer, PTEN and the PI-3 kinase pathway. Semin. Cell Dev. Biol. 15, 171-176 (2004). 

  38. Oncogene CB Knobbe 27 5398 2008 10.1038/onc.2008.238 Knobbe, C. B., Lapin, V., Suzuki, A. & Mak, T. W. The roles of PTEN in development, physiology and tumorigenesis in mouse models: a tissue-by-tissue survey. Oncogene 27, 5398-5415 (2008). 

  39. Science J Li 275 1943 1997 10.1126/science.275.5308.1943 Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943-1947 (1997). 

  40. Nature Genet. A Di Cristofano 27 222 2001 10.1038/84879 Di Cristofano, A., De Acetis, M., Koff, A., Cordon-Cardo, C. & Pandolfi, P. P. Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nature Genet. 27, 222-224 (2001). 

  41. Nature Genet. A Di Cristofano 19 348 1998 10.1038/1235 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). 

  42. Cancer Cell S Wang 4 209 2003 10.1016/S1535-6108(03)00215-0 Wang, S. et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4, 209-221 (2003). 

  43. Cancer Res. V Stambolic 60 3605 2000 Stambolic, V. et al. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/− mice. Cancer Res. 60, 3605-3611 (2000). 

  44. Cancer Res. K Stemke-Hale 68 6084 2008 10.1158/0008-5472.CAN-07-6854 Stemke-Hale, K. et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 68, 6084-6091 (2008). 

  45. Proc. Natl Acad. Sci. USA JJ Zhao 102 18443 2005 10.1073/pnas.0508988102 Zhao, J. J. et al. The oncogenic properties of mutant p110α and p110β phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc. Natl Acad. Sci. USA 102, 18443-18448 (2005). 

  46. Cancer Res. SJ Isakoff 65 10992 2005 10.1158/0008-5472.CAN-05-2612 Isakoff, S. J. et al. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 65, 10992-11000 (2005). 

  47. Cancer Cell Y Samuels 7 561 2005 10.1016/j.ccr.2005.05.014 Samuels, Y. et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7, 561-573 (2005). 

  48. Proc. Natl Acad. Sci. USA AG Bader 103 1475 2006 10.1073/pnas.0510857103 Bader, A. G., Kang, S. & Vogt, P. K. Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc. Natl Acad. Sci. USA 103, 1475-1479 (2006). 

  49. Science JY Lee 317 206 2007 10.1126/science.1146073 Lee, J. Y., Engelman, J. A. & Cantley, L. C. Biochemistry. PI3K charges ahead. Science 317, 206-207 (2007). 

  50. Cell Cycle CH Huang 7 1151 2008 10.4161/cc.7.9.5817 Huang, C. H., Mandelker, D., Gabelli, S. B. & Amzel, L. M. Insights into the oncogenic effects of PIK3CA mutations from the structure of p110α/p85α. Cell Cycle 7, 1151-1156 (2008). 

  51. Science N Miled 317 239 2007 10.1126/science.1135394 Miled, N. et al. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317, 239-242 (2007). 

  52. Science CH Huang 318 1744 2007 10.1126/science.1150799 Huang, C. H. et al. The structure of a human p110α/p85α complex elucidates the effects of oncogenic PI3Kα mutations. Science 318, 1744-1748 (2007). References 51 and 52 report crystal structural analyses of p110α and p85 iSH2 domains to help elucidate the effects of the cancer-associated mutations in p110α. 

  53. Brain Pathol. M Mizoguchi 14 372 2004 10.1111/j.1750-3639.2004.tb00080.x Mizoguchi, M., Nutt, C. L., Mohapatra, G. & Louis, D. N. Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas. Brain Pathol. 14, 372-377 (2004). 

  54. Cancer Res. AJ Philp 61 7426 2001 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). 

  55. Biochem. J. CA Beeton 350 353 2000 10.1042/bj3500353 Beeton, C. A., Chance, E. M., Foukas, L. C. & Shepherd, P. R. Comparison of the kinetic properties of the lipid- and protein-kinase activities of the p110α and p110β catalytic subunits of class-Ia phosphoinositide 3-kinases. Biochem. J. 350, 353-359 (2000). 

  56. Oncogene C Benistant 19 5083 2000 10.1038/sj.onc.1203871 Benistant, C., Chapuis, H. & Roche, S. A specific function for phosphatidylinositol 3-kinase α (p85α-p110α) in cell survival and for phosphatidylinositol 3-kinase β (p85α-p110b) in de novo DNA synthesis of human colon carcinoma cells. Oncogene 19, 5083-5090 (2000). 

  57. Cancer Cell J Brugge 12 104 2007 10.1016/j.ccr.2007.07.014 Brugge, J., Hung., M. C. & Mills, G. B. A new mutational AKTivation in the PI3K pathway. Cancer Cell 12, 104-107 (2007). 

  58. Nature JD Carpten 448 439 2007 10.1038/nature05933 Carpten, J. D. et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448, 439-444 (2007). This paper describes the identification of an activating AKT1 mutation in human cancer. 

  59. Br. J. Cancer MA Davies 99 1265 2008 10.1038/sj.bjc.6604637 Davies, M. A. et al. A novel AKT3 mutation in melanoma tumours and cell lines. Br. J. Cancer 99, 1265-1268 (2008). 

  60. Biochem. J. B Vanhaesebroeck 346 561 2000 10.1042/bj3460561 Vanhaesebroeck, B. & Alessi, D. R. The PI3K-PDK1 connection: more than just a road to PKB. Biochem. J. 346, 561-576 (2000). 

  61. Cancer Res. C Hunter 66 3987 2006 10.1158/0008-5472.CAN-06-0127 Hunter, C. et al. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 66, 3987-3991 (2006). 

  62. Biochem. Soc. Trans. ZA Knight 35 245 2007 10.1042/BST0350245 Knight, Z. A. & Shokat, K. M. Chemically targeting the PI3K family. Biochem. Soc. Trans. 35, 245-249 (2007). 

  63. Biochim. Biophys. Acta R Marone 1784 159 2008 10.1016/j.bbapap.2007.10.003 Marone, R., Cmiljanovic, V., Giese, B. & Wymann, M. P. Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim. Biophys. Acta 1784, 159-185 (2008). 

  64. Cell ZA Knight 125 733 2006 10.1016/j.cell.2006.03.035 Knight, Z. A. et al. A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling. Cell 125, 733-747 (2006). A comparative analysis of the roles of PI3K isoforms using small-molecule inhibitors. 

  65. Cancer Cell QW Fan 9 341 2006 10.1016/j.ccr.2006.03.029 Fan, Q. W. et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9, 341-349 (2006). 

  66. Mol. Cancer Ther. SM Maira 7 1851 2008 10.1158/1535-7163.MCT-08-0017 Maira, S. M. et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther. 7, 1851-1863 (2008). 

  67. Cancer Res. V Serra 68 8022 2008 10.1158/0008-5472.CAN-08-1385 Serra, V. et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 68, 8022-8030 (2008). 

  68. Oncogene C Garcia-Echeverria 27 5511 2008 10.1038/onc.2008.246 Garcia-Echeverria, C. & Sellers, W. R. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27, 5511-5526 (2008). 

  69. Cancer Res. JR Garlich 68 206 2008 10.1158/0008-5472.CAN-07-0669 Garlich, J. R. et al. A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res. 68, 206-215 (2008). 

  70. Mol. Cancer Ther. NT Ihle 4 1349 2005 10.1158/1535-7163.MCT-05-0149 Ihle, N. T. et al. The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. Mol. Cancer Ther. 4, 1349-1357 (2005). 

  71. Eur. J. Cancer P Hilgard 33 442 1997 10.1016/S0959-8049(97)89020-X Hilgard, P. et al. D-21266, a new heterocyclic alkylphospholipid with antitumour activity. Eur. J. Cancer 33, 442-446 (1997). 

  72. Oncol. Res. EJ Meuillet 14 513 2004 10.3727/0965040042380487 Meuillet, E. J. et al. In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316. Oncol. Res. 14, 513-527 (2004). 

  73. Expert Opin. Investig. Drugs JJ Gills 13 787 2004 10.1517/13543784.13.7.787 Gills, J. J. & Dennis, P. A. The development of phosphatidylinositol ether lipid analogues as inhibitors of the serine/threonine kinase, Akt. Expert Opin. Investig. Drugs 13, 787-797 (2004). 

  74. Mol. Cancer Ther. JJ Gills 5 713 2006 10.1158/1535-7163.MCT-05-0484 Gills, J. J. et al. Spectrum of activity and molecular correlates of response to phosphatidylinositol ether lipid analogues, novel lipid-based inhibitors of Akt. Mol. Cancer Ther. 5, 713-722 (2006). 

  75. Cancer Res. N Rhodes 68 2366 2008 10.1158/0008-5472.CAN-07-5783 Rhodes, N. et al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res. 68, 2366-2374 (2008). 

  76. Curr. Top. Med. Chem. CW Lindsley 7 1349 2007 10.2174/156802607782507439 Lindsley, C. W., Barnett, S. F., Yaroschak, M., Bilodeau, M. T. & Layton, M. E. Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors. Curr. Top. Med. Chem. 7, 1349-1363 (2007). 

  77. Cancer Res. H Yang 68 425 2008 10.1158/0008-5472.CAN-07-2488 Yang, H. et al. MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res. 68, 425-433 (2008). 

  78. J. Antibiot. (Tokyo) C Vezina 28 721 1975 10.7164/antibiotics.28.721 Vezina, C., Kudelski, A. & Sehgal, S. N. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. (Tokyo) 28, 721-726 (1975). 

  79. Ther. Drug Monit. RW Yatscoff 15 478 1993 10.1097/00007691-199312000-00004 Yatscoff, R. W., LeGatt, D. F. & Kneteman, N. M. Therapeutic monitoring of rapamycin: a new immunosuppressive drug. Ther. Drug Monit. 15, 478-482 (1993). 

  80. Nature Rev. Drug Discov. S Faivre 5 671 2006 10.1038/nrd2062 Faivre, S., Kroemer, G. & Raymond, E. Current development of mTOR inhibitors as anticancer agents. Nature Rev. Drug Discov. 5, 671-688 (2006). 

  81. Cancer Cell DA Guertin 12 9 2007 10.1016/j.ccr.2007.05.008 Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9-22 (2007). 

  82. Cancer Cell N Hay 8 179 2005 10.1016/j.ccr.2005.08.008 Hay, N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 8, 179-183 (2005). 

  83. J. Clin. Oncol. MB Atkins 22 909 2004 10.1200/JCO.2004.08.185 Atkins, M. B. et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J. Clin. Oncol. 22, 909-918 (2004). 

  84. Cancer Cell DA Guertin 15 148 2009 10.1016/j.ccr.2008.12.017 Guertin, D. A. et al. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 15, 148-159 (2009). 

  85. PLoS Biol. ME Feldman 7 e38 2009 10.1371/journal.pbio.1000038 Feldman, M. E. et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7, e38 (2009). 

  86. J. Biol. Chem. CC Thoreen 284 8023 2009 10.1074/jbc.M900301200 Thoreen, C. C. et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023-8032 (2009). 

  87. J. Biol. Chem. N Fujita 277 10346 2002 10.1074/jbc.M106736200 Fujita, N., Sato, S., Ishida, A. & Tsuruo, T. Involvement of Hsp90 in signaling and stability of 3-phosphoinositide-dependent kinase-1. J. Biol. Chem. 277, 10346-10353 (2002). 

  88. Cancer Res. DB Solit 63 2139 2003 Solit, D. B., Basso, A. D., Olshen, A. B., Scher, H. I. & Rosen, N. Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. Cancer Res. 63, 2139-2144 (2003). 

  89. Curr. Top. Med. Chem. DB Solit 6 1205 2006 10.2174/156802606777812068 Solit, D. B. & Rosen, N. Hsp90: a novel target for cancer therapy. Curr. Top. Med. Chem. 6, 1205-1214 (2006). 

  90. Ann. NY Acad. Sci. P Workman 1113 202 2007 10.1196/annals.1391.012 Workman, P., Burrows, F., Neckers, L. & Rosen, N. Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann. NY Acad. Sci. 1113, 202-216 (2007). 

  91. Mamm. Genome L Bi 13 169 2002 Bi, L., Okabe, I., Bernard, D. J. & Nussbaum, R. L. Early embryonic lethality in mice deficient in the p110β catalytic subunit of PI 3-kinase. Mamm. Genome 13, 169-172 (2002). 

  92. J. Biol. Chem. L Bi 274 10963 1999 10.1074/jbc.274.16.10963 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). 

  93. 10.1038/nature07091 Jia, S. et al. Essential roles of PI3K-p110β in cell growth, metabolism and tumorigenesis. Nature (2008). This study showed that p110β, not p110α, contributed to PTEN-deficiency-induced prostate cancer in mouse genetic models. 

  94. Proc. Natl Acad. Sci. USA JJ Zhao 103 16296 2006 10.1073/pnas.0607899103 Zhao, J. J. et al. The p110α isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc. Natl Acad. Sci. USA 103, 16296-16300 (2006). 

  95. Sci. Signal E Ciraolo 1 ra3 2008 10.1126/scisignal.1161577 Ciraolo, E. et al. Phosphoinositide 3-kinase p110β activity: key role in metabolism and mammary gland cancer but not development. Sci. Signal 1, ra3 (2008). A study on the role of p110β in metabolism and Her2-induced breast cancer using a knock-in mouse model. 

  96. Proc. Natl Acad. Sci. USA J Guillermet-Guibert 105 8292 2008 10.1073/pnas.0707761105 Guillermet-Guibert, J. et al. The p110β isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110γ. Proc. Natl Acad. Sci. USA 105, 8292-8297 (2008). 

  97. Nature M Graupera 453 662 2008 10.1038/nature06892 Graupera, M. et al. Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration. Nature 453, 662-666 (2008). This work demonstrated a specific role of p110α in endothelial cell migration. 

  98. Nature LC Foukas 441 366 2006 10.1038/nature04694 Foukas, L. C. et al. Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441, 366-370 (2006). This study showed the role of p110α in insulin signaling and metabolism using an inactive-kinase knock-in mouse model. 

  99. J. Virol. T Utermark 81 7069 2007 10.1128/JVI.00115-07 Utermark, T., Schaffhausen, B. S., Roberts, T. M. & Zhao, J. J. The p110α isoform of phosphatidylinositol 3-kinase is essential for polyomavirus middle T antigen-mediated transformation. J. Virol. 81, 7069-7076 (2007). 

  100. Nature Med. SP Jackson 11 507 2005 10.1038/nm1232 Jackson, S. P. et al. PI3-kinase p110β: a new target for antithrombotic therapy. Nature Med. 11, 507-514 (2005). 

  101. Curr. Opin. Pharmacol. TA Yap 8 393 2008 10.1016/j.coph.2008.08.004 Yap, T. A. et al. Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr. Opin. Pharmacol. 8, 393-412 (2008). 

  102. Biochem. J. NE Torbett 415 97 2008 10.1042/BJ20080639 Torbett, N. E. et al. 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 (2008). 

  103. Proc. Natl Acad. Sci. USA S Wee 105 13057 2008 10.1073/pnas.0802655105 Wee, S. et al. PTEN-deficient cancers depend on PIK3CB. Proc. Natl Acad. Sci. USA 105, 13057-13062 (2008). 

  104. Cancer Res. K Oda 68 8127 2008 10.1158/0008-5472.CAN-08-0755 Oda, K. et al. PIK3CA cooperates with other phosphatidylinositol 3-kinase pathway mutations to effect oncogenic transformation. Cancer Res. 68, 8127-8136 (2008). 

  105. J. Biol. Chem. V Aguirre 275 9047 2000 10.1074/jbc.275.12.9047 Aguirre, V., Uchida, T., Yenush, L., Davis, R. & White, M. F. The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J. Biol. Chem. 275, 9047-9054 (2000). 

  106. Trends Biochem. Sci. LS Harrington 30 35 2005 10.1016/j.tibs.2004.11.003 Harrington, L. S., Findlay, G. M. & Lamb, R. F. Restraining PI3K: mTOR signalling goes back to the membrane. Trends Biochem. Sci. 30, 35-42 (2005). 

  107. J. Biol. Chem. YH Lee 278 2896 2003 10.1074/jbc.M208359200 Lee, Y. H., Giraud, J., Davis, R. J. & White, M. F. c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J. Biol. Chem. 278, 2896-2902 (2003). 

  108. Nature J Hirosumi 420 333 2002 10.1038/nature01137 Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333-336 (2002). 

  109. Nature SH Um 431 200 2004 10.1038/nature02866 Um, S. H. et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200-205 (2004). 

  110. Cancer Res. KE OReilly 66 1500 2006 10.1158/0008-5472.CAN-05-2925 OReilly, K. E. et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 1500-1508 (2006). 

  111. Sci. STKE T Jun 1999 PE1 1999 Jun, T., Gjoerup, O. & Roberts, T. M. Tangled webs: evidence of cross-talk between c-Raf-1 and Akt. Sci. STKE 1999, PE1 (1999). 

  112. J. Clin. Invest. A Carracedo 118 3065 2008 Carracedo, A. et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J. Clin. Invest. 118, 3065-3074 (2008). 

  113. Cancer Chemother. Pharmacol. R Williams 58 444 2006 10.1007/s00280-006-0190-0 Williams, R. et al. The skin and hair as surrogate tissues for measuring the target effect of inhibitors of phosphoinositide-3-kinase signaling. Cancer Chemother. Pharmacol. 58, 444-450 (2006). 

  114. Science H Cho 292 1728 2001 10.1126/science.292.5522.1728 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). 

  115. Mol. Cell Biol. SM Brachmann 25 1596 2005 10.1128/MCB.25.5.1596-1607.2005 Brachmann, S. M., Ueki, K., Engelman, J. A., Kahn, R. C. & Cantley, L. C. Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. Mol. Cell Biol. 25, 1596-1607 (2005). 

  116. Cancer Res. CR Schnell 68 6598 2008 10.1158/0008-5472.CAN-08-1044 Schnell, C. R. et al. Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res. 68, 6598-6607 (2008). 

  117. Lancet Oncol. JB Bomanji 2 157 2001 10.1016/S1470-2045(00)00257-6 Bomanji, J. B., Costa, D. C. & Ell, P. J. Clinical role of positron emission tomography in oncology. Lancet Oncol. 2, 157-164 (2001). 

  118. Cancer Res. PJ Eichhorn 68 9221 2008 10.1158/0008-5472.CAN-08-1740 Eichhorn, P. J. et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 68, 9221-9230 (2008). 

  119. Cancer Cell K Berns 12 395 2007 10.1016/j.ccr.2007.08.030 Berns, K. et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12, 395-402 (2007). 

  120. Nature Rev. Cancer J Zhang 9 28 2009 10.1038/nrc2559 Zhang, J., Yang, P. L. & Gray, N. S. Targeting cancer with small molecule kinase inhibitors. Nature Rev. Cancer 9, 28-39 (2009). 

  121. Cancer Cell ER Zunder 14 180 2008 10.1016/j.ccr.2008.06.014 Zunder, E. R., Knight, Z. A., Houseman, B. T., Apsel, B. & Shokat, K. M. Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110α. Cancer Cell 14, 180-192 (2008). 

  122. Proc. Natl Acad. Sci. USA JA Engelman 102 3788 2005 10.1073/pnas.0409773102 Engelman, J. A. et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc. Natl Acad. Sci. USA 102, 3788-3793 (2005). 

  123. Science JA Engelman 316 1039 2007 10.1126/science.1141478 Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039-1043 (2007). 

  124. Nature NV Sergina 445 437 2007 10.1038/nature05474 Sergina, N. V. et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445, 437-441 (2007). 

  125. Nature Chem. Biol. B Apsel 4 691 2008 10.1038/nchembio.117 Apsel, B. et al. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nature Chem. Biol. 4, 691-699 (2008). 

  126. Cell S Gupta 129 957 2007 10.1016/j.cell.2007.03.051 Gupta, S. et al. Binding of ras to phosphoinositide 3-kinase p110a is required for ras-driven tumorigenesis in mice. Cell 129, 957-968 (2007). 

  127. Nature Med. JA Engelman 14 1351 2008 10.1038/nm.1890 Engelman, J. A. et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nature Med. 14, 1351-1356 (2008). This study showned that a combined treatment with PI3K and MEK inhibitors is necessary to block oncogenic Kras -induced lung cancer in a murine model. 

  128. Cancer Biol. Ther. K Yu 7 307 2008 Yu, K., Toral-Barza, L., Shi, C., Zhang, W. G. & Zask, A. Response and determinants of cancer cell susceptibility to PI3K inhibitors: combined targeting of PI3K and Mek1 as an effective anticancer strategy. Cancer Biol. Ther. 7, 307-315 (2008). 

  129. Proc. Natl Acad. Sci. USA TL Yuan 105 9739 2008 10.1073/pnas.0804123105 Yuan, T. L. et al. Class 1A PI3K regulates vessel integrity during development and tumorigenesis. Proc. Natl Acad. Sci. USA 105, 9739-9744 (2008). 

  130. Nature Med. M Guba 8 128 2002 10.1038/nm0202-128 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). 

  131. N. Engl. J. Med. G Stallone 352 1317 2005 10.1056/NEJMoa042831 Stallone, G. et al. Sirolimus for Kaposis sarcoma in renal-transplant recipients. N. Engl. J. Med. 352, 1317-1323 (2005). 

  132. Nature Med. GV Thomas 12 122 2006 10.1038/nm1337 Thomas, G. V. et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nature Med. 12, 122-127 (2006). 

  133. Mol. Cell Biol. CC Hudson 22 7004 2002 10.1128/MCB.22.20.7004-7014.2002 Hudson, C. C. et al. Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol. Cell Biol. 22, 7004-7014 (2002). 

  134. Nature R Bernardi 442 779 2006 10.1038/nature05029 Bernardi, R. et al. PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR. Nature 442, 779-785 (2006). 

  135. Cancer Cell TL Phung 10 159 2006 10.1016/j.ccr.2006.07.003 Phung, T. L. et al. Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 10, 159-170 (2006). 

  136. Genes Dev. K Hamada 19 2054 2005 10.1101/gad.1308805 Hamada, K. et al. The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. Genes Dev. 19, 2054-2065 (2005). 

  137. Curr. Biol. JR Bayascas 15 1839 2005 10.1016/j.cub.2005.08.066 Bayascas, J. R., Leslie, N. R., Parsons, R., Fleming, S. & Alessi, D. R. Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN+/− mice. Curr. Biol. 15, 1839-1846 (2005). 

  138. Genes Dev. ML Chen 20 1569 2006 10.1101/gad.1395006 Chen, M. L. et al. The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/− mice. Genes Dev. 20, 1569-1574 (2006). 

  139. Cancer Res. PP Massion 62 3636 2002 Massion, P. P. et al. Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridization: implications of the phosphatidylinositol 3-kinase pathway. Cancer Res. 62, 3636-3640 (2002). 

  140. Am. J. Respir. Crit. Care Med. PP Massion 170 1088 2004 10.1164/rccm.200404-487OC Massion, P. P. et al. Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer progression. Am. J. Respir. Crit. Care Med. 170, 1088-1094 (2004). 

  141. Pathol. Int. K Okudela 57 664 2007 10.1111/j.1440-1827.2007.02155.x Okudela, K. et al. PIK3CA mutation and amplification in human lung cancer. Pathol. Int. 57, 664-671 (2007). 

  142. Lung Cancer O Kawano 58 159 2007 10.1016/j.lungcan.2007.06.020 Kawano, O. et al. PIK3CA gene amplification in Japanese non-small cell lung cancer. Lung Cancer 58, 159-160 (2007). 

  143. Oncogene YY Ma 19 2739 2000 10.1038/sj.onc.1203597 Ma, Y. Y. et al. PIK3CA as an oncogene in cervical cancer. Oncogene 19, 2739-2744 (2000). 

  144. Breast Cancer Res. G Wu 7 R609 2005 10.1186/bcr1262 Wu, G. et al. Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res. 7, R609-R616 (2005). 

  145. J. Pathol. J Woenckhaus 198 335 2002 10.1002/path.1207 Woenckhaus, J. et al. Genomic gain of PIK3CA and increased expression of p110α are associated with progression of dysplasia into invasive squamous cell carcinoma. J. Pathol. 198, 335-342 (2002). 

  146. Int. J. Cancer JM Pedrero 114 242 2005 10.1002/ijc.20711 Pedrero, J. M. et al. Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Int. J. Cancer 114, 242-248 (2005). 

  147. Oncol. Rep. I Fenic 18 253 2007 Fenic, I., Steger, K., Gruber, C., Arens, C. & Woenckhaus, J. Analysis of PIK3CA and Akt/protein kinase B in head and neck squamous cell carcinoma. Oncol. Rep. 18, 253-259 (2007). 

  148. Int. J. Cancer DS Byun 104 318 2003 10.1002/ijc.10962 Byun, D. S. et al. Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIK3CA amplification in gastric carcinoma. Int. J. Cancer 104, 318-327 (2003). 

  149. J. Clin. Endocrinol. Metab. G Wu 90 4688 2005 10.1210/jc.2004-2281 Wu, G. et al. Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors. J. Clin. Endocrinol. Metab. 90, 4688-4693 (2005). 

  150. Clin. Cancer Res. CT Miller 9 4819 2003 Miller, C. T. et al. Gene amplification in esophageal adenocarcinomas and Barretts with high-grade dysplasia. Clin. Cancer Res. 9, 4819-4825 (2003). 

  151. Cancer Lett. T Miyake 261 120 2008 10.1016/j.canlet.2007.11.004 Miyake, T. et al. PIK3CA gene mutations and amplifications in uterine cancers, identified by methods that avoid confounding by PIK3CA pseudogene sequences. Cancer Lett. 261, 120-126 (2008). 

  152. Int. J. Cancer K Nakayama 120 2613 2007 10.1002/ijc.22609 Nakayama, K. et al. Amplicon profiles in ovarian serous carcinomas. Int. J. Cancer 120, 2613-2617 (2007). 

  153. Cancer Biol. Ther. K Nakayama 5 779 2006 10.4161/cbt.5.7.2751 Nakayama, K. et al. Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms. Cancer Biol. Ther. 5, 779-785 (2006). 

  154. Acta Neuropathol. D Kita 113 295 2007 10.1007/s00401-006-0186-1 Kita, D., Yonekawa, Y., Weller, M. & Ohgaki, H. PIK3CA alterations in primary (de novo) and secondary glioblastomas. Acta Neuropathol. 113, 295-302 (2007). 

  155. Oncogene FE Bleeker 27 5648 2008 10.1038/onc.2008.170 Bleeker, F. E. et al. AKT1E17K in human solid tumours. Oncogene 27, 5648-5650 (2008). 

  156. Br. J. Cancer MS Kim 98 1533 2008 10.1038/sj.bjc.6604212 Kim, M. S., Jeong, E. G., Yoo, N. J. & Lee, S. H. Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias. Br. J. Cancer 98, 1533-1535 (2008). 

  157. Cell Cycle D Malanga 7 665 2008 10.4161/cc.7.5.5485 Malanga, D. et al. Activating E17K mutation in the gene encoding the protein kinase AKT1 in a subset of squamous cell carcinoma of the lung. Cell Cycle 7, 665-669 (2008). 

  158. Proc. Natl Acad. Sci. USA SP Staal 84 5034 1987 10.1073/pnas.84.14.5034 Staal, S. P. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc. Natl Acad. Sci. USA 84, 5034-5037 (1987). 

  159. Int. J. Cancer A Bellacosa 64 280 1995 10.1002/ijc.2910640412 Bellacosa, A. et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int. J. Cancer 64, 280-285 (1995). 

  160. Proc. Natl Acad. Sci. USA JQ Cheng 89 9267 1992 10.1073/pnas.89.19.9267 Cheng, J. Q. et al. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc. Natl Acad. Sci. USA 89, 9267-9271 (1992). 

  161. Mol. Carcinog. BA Ruggeri 21 81 1998 10.1002/(SICI)1098-2744(199802)21:2<81::AID-MC1>3.0.CO;2-R 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). 

  162. J. Gastroenterol. Hepatol. E Oki 21 814 2006 10.1111/j.1440-1746.2005.04028.x Oki, E. et al. Impact of loss of heterozygosity of encoding phosphate and tensin homolog on the prognosis of gastric cancer. J. Gastroenterol. Hepatol. 21, 814-818 (2006). 

  163. World J. Gastroenterol. YL Li 11 285 2005 10.3748/wjg.v11.i2.285 Li, Y. L., Tian, Z., Wu, D. Y., Fu, B. Y. & Xin, Y. Loss of heterozygosity on 10q23.3 and mutation of tumor suppressor gene PTEN in gastric cancer and precancerous lesions. World J. Gastroenterol. 11, 285-288 (2005). 

  164. Br. J. Cancer HE Feilotter 79 718 1999 10.1038/sj.bjc.6690115 Feilotter, H. E. et al. Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma. Br. J. Cancer 79, 718-723 (1999). 

  165. Br. J. Cancer D Freihoff 79 754 1999 10.1038/sj.bjc.6690121 Freihoff, D. et al. Exclusion of a major role for the PTEN tumour-suppressor gene in breast carcinomas. Br. J. Cancer 79, 754-758 (1999). 

  166. Breast Cancer Res. Treat. JM Garcia 57 237 1999 10.1023/A:1006273516976 Garcia, J. M. et al. Allelic loss of the PTEN region (10q23) in breast carcinomas of poor pathophenotype. Breast Cancer Res. Treat. 57, 237-243 (1999). 

  167. Breast Cancer Res. Treat. E Tokunaga 101 249 2007 10.1007/s10549-006-9295-8 Tokunaga, E. et al. Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma. Breast Cancer Res. Treat. 101, 249-257 (2007). 

  168. Melanoma Res. PM Pollock 12 565 2002 10.1097/00008390-200212000-00006 Pollock, P. M. et al. PTEN inactivation is rare in melanoma tumours but occurs frequently in melanoma cell lines. Melanoma Res. 12, 565-575 (2002). 

  169. J. Med. Genet. JT Celebi 37 653 2000 10.1136/jmg.37.9.653 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). 

  170. J. Invest. Dermatol. A Birck 114 277 2000 10.1046/j.1523-1747.2000.00877.x Birck, A., Ahrenkiel, V., Zeuthen, J., Hou-Jensen, K. & Guldberg, P. Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. J. Invest. Dermatol. 114, 277-280 (2000). 

  171. Virchows Arch. J Reifenberger 436 487 2000 10.1007/s004280050477 Reifenberger, J. et al. Allelic losses on chromosome arm 10q and mutation of the PTEN (MMAC1) tumour suppressor gene in primary and metastatic malignant melanomas. Virchows Arch. 436, 487-493 (2000). 

  172. Cancer Res. P Cairns 57 4997 1997 Cairns, P. et al. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res. 57, 4997-5000 (1997). 

  173. Oncogene HE Feilotter 16 1743 1998 10.1038/sj.onc.1200205 Feilotter, H. E., Nagai, M. A., Boag, A. H., Eng, C. & Mulligan, L. M. Analysis of PTEN and the 10q23 region in primary prostate carcinomas. Oncogene 16, 1743-1748 (1998). 

  174. Oncogene S Pesche 16 2879 1998 10.1038/sj.onc.1202081 Pesche, S. et al. PTEN/MMAC1/TEP1 involvement in primary prostate cancers. Oncogene 16, 2879-2883 (1998). 

  175. Br. J. Cancer IC Gray 78 1296 1998 10.1038/bjc.1998.674 Gray, I. C. et al. Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN. Br. J. Cancer 78, 1296-1300 (1998). 

  176. Clin. Cancer Res. SI Wang 4 811 1998 Wang, S. I., Parsons, R. & Ittmann, M. Homozygous deletion of the PTEN tumor suppressor gene in a subset of prostate adenocarcinomas. Clin. Cancer Res. 4, 811-815 (1998). 

  177. Cancer Res. J Bostrom 58 29 1998 Bostrom, J. et al. Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q. Cancer Res. 58, 29-33 (1998). 

  178. Cancer Res. SI Wang 57 4183 1997 Wang, S. I. et al. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 57, 4183-4186 (1997). 

  179. J. Natl Cancer Inst. JS Smith 93 1246 2001 10.1093/jnci/93.16.1246 Smith, J. S. et al. PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J. Natl Cancer Inst. 93, 1246-1256 (2001). 

  180. Blood N Kim 110 3202 2007 10.1182/blood-2007-02-075366 Kim, N. et al. The p110δ catalytic isoform of PI3K is a key player in NK-cell development and cytokine secretion. Blood 110, 3202-3208 (2007). 

  181. J. Exp. Med. E Clayton 196 753 2002 10.1084/jem.20020805 Clayton, E. et al. A crucial role for the p110δ subunit of phosphatidylinositol 3-kinase in B cell development and activation. J. Exp. Med. 196, 753-763 (2002). 

  182. Mol. Cell Biol. ST Jou 22 8580 2002 10.1128/MCB.22.24.8580-8591.2002 Jou, S. T. et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the B-cell receptor complex. Mol. Cell Biol. 22, 8580-8591 (2002). 

  183. Blood KD Puri 103 3448 2004 10.1182/blood-2003-05-1667 Puri, K. D. et al. Mechanisms and implications of phosphoinositide 3-kinase delta in promoting neutrophil trafficking into inflamed tissue. Blood 103, 3448-3456 (2004). 

  184. Science K Okkenhaug 297 1031 2002 10.1126/science.1073560 Okkenhaug, K. et al. Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science 297, 1031-1034 (2002). 

  185. Nature K Ali 431 1007 2004 10.1038/nature02991 Ali, K. et al. Essential role for the p110δ phosphoinositide 3-kinase in the allergic response. Nature 431, 1007-1011 (2004). 

  186. J. Exp. Med. H Guo 205 2419 2008 10.1084/jem.20072327 Guo, H., Samarakoon, A., Vanhaesebroeck, B. & Malarkannan, S. The p110δ of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation. J. Exp. Med. 205, 2419-2435 (2008). 

  187. Science E Hirsch 287 1049 2000 10.1126/science.287.5455.1049 Hirsch, E. et al. Central role for G protein-coupled phosphoinositide 3-kinase γ in inflammation. Science 287, 1049-1053 (2000). 

  188. Endocrinology PE MacDonald 145 4078 2004 10.1210/en.2004-0028 MacDonald, P. E. et al. Impaired glucose-stimulated insulin secretion, enhanced intraperitoneal insulin tolerance, and increased β-cell mass in mice lacking the p110γ isoform of phosphoinositide 3-kinase. Endocrinology 145, 4078-4083 (2004). 

  189. Cell MA Crackower 110 737 2002 10.1016/S0092-8674(02)00969-8 Crackower, M. A. et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110, 737-749 (2002). 

  190. Science Z Li 287 1046 2000 10.1126/science.287.5455.1046 Li, Z. et al. Roles of PLC-β2 and -β3 and PI3Kγ in chemoattractant-mediated signal transduction. Science 287, 1046-1049 (2000). 

  191. Immunity M Laffargue 16 441 2002 10.1016/S1074-7613(02)00282-0 Laffargue, M. et al. Phosphoinositide 3-kinase γ is an essential amplifier of mast cell function. Immunity 16, 441-451 (2002). 

  192. J. Immunol. L Rodriguez-Borlado 170 4475 2003 10.4049/jimmunol.170.9.4475 Rodriguez-Borlado, L. et al. Phosphatidylinositol 3-kinase regulates the CD4/CD8 T cell differentiation ratio. J. Immunol. 170, 4475-4482 (2003). 

  193. J. Immunol. LM Webb 175 2783 2005 10.4049/jimmunol.175.5.2783 Webb, L. M., Vigorito, E., Wymann, M. P., Hirsch, E. & Turner, M. Cutting edge: T cell development requires the combined activities of the p110γ and p110δ catalytic isoforms of phosphatidylinositol 3-kinase. J. Immunol. 175, 2783-2787 (2005). 

  194. Blood W Swat 107 2415 2006 10.1182/blood-2005-08-3300 Swat, W. et al. Essential role of PI3Kδ and PI3Kγ in thymocyte survival. Blood 107, 2415-2422 (2006). 

  195. Immunity I Tassi 27 214 2007 10.1016/j.immuni.2007.07.014 Tassi, I. et al. p110γ and p110δ phosphoinositide 3-kinase signaling pathways synergize to control development and functions of murine NK cells. Immunity 27, 214-227 (2007). 

  196. Nature Genet. Y Terauchi 21 230 1999 10.1038/6023 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). 

  197. Science H Suzuki 283 390 1999 10.1126/science.283.5400.390 Suzuki, H. et al. Xid-like immunodeficiency in mice with disruption of the p85α subunit of phosphoinositide 3-kinase. Science 283, 390-392 (1999). 

  198. Mol. Cell Biol. D Chen 24 320 2004 10.1128/MCB.24.1.320-329.2004 Chen, D. et al. p50α/p55α phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity. Mol. Cell Biol. 24, 320-329 (2004). 

  199. Science DA Fruman 283 393 1999 10.1126/science.283.5400.393 Fruman, D. A. et al. Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85α. Science 283, 393-397 (1999). 

  200. Nature Genet. DA Fruman 26 379 2000 10.1038/81715 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). 

  201. Proc. Natl Acad. Sci. USA K Ueki 99 419 2002 10.1073/pnas.012581799 Ueki, K. et al. Increased insulin sensitivity in mice lacking p85β subunit of phosphoinositide 3-kinase. Proc. Natl Acad. Sci. USA 99, 419-424 (2002). 

  202. Cell. Metab. CM Taniguchi 3 343 2006 10.1016/j.cmet.2006.04.005 Taniguchi, C. M. et al. Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKCλ/ζ. Cell. Metab. 3, 343-353 (2006). 

  203. Cell Metab. J Luo 3 355 2006 10.1016/j.cmet.2006.04.003 Luo, J. et al. Loss of class IA PI3K signaling in muscle leads to impaired muscle growth, insulin response, and hyperlipidemia. Cell Metab. 3, 355-366 (2006). 

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