Ras, PI(3)K and mTOR signalling controls tumour cell growth

Nature

Volumn 441, Issue 7092, 2006, Pages 424-430

  Shaw, Reuben J ^a   Cantley, Lewis C ^b,c  

^a SALK INSTITUTE FOR BIOLOGICAL STUDIES   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACIDS; CELL CULTURE; GLUCOSE; NUTRITION; PROTEINS; TUMORS;

EUKARYOTIC CELLS; PHOSPHATIDYLINOSITOL-3-OH KINASE (PI(3)K); TUMOUR CELL GROWTH;

CELLS;

AMINO ACID; EPIDERMAL GROWTH FACTOR RECEPTOR 3; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; OXYGEN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE LKB1; RAF PROTEIN; RAPAMYCIN; RAS PROTEIN; TUBERIN; WORTMANNIN; PROTEIN KINASE;

AMINO ACID; ENZYME ACTIVITY; EUKARYOTE; GLUCOSE; GROWTH RATE; MUTATION; NUTRIENT AVAILABILITY; TUMOR;

CANCER GROWTH; CANCER RESEARCH; CARCINOGENESIS; CELL METABOLISM; CELL SURVIVAL; COLON CANCER; COWDEN SYNDROME; DIABETES MELLITUS; ENZYME ACTIVATION; ENZYME ACTIVITY; GENE MUTATION; GLUCOSE TRANSPORT; GROWTH INHIBITION; HAMARTOMA; HEMANGIOMA; HUMAN; HYPOXIA; INSULIN RESISTANCE; MAMMAL; MELANOMA; MOUSE STRAIN; NONHUMAN; OBESITY; PEUTZ JEGHERS SYNDROME; PHOSPHORYLATION; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; TUBEROUS SCLEROSIS; TUMOR GROWTH; YEAST; ANIMAL; CELL GROWTH; METABOLISM; NEOPLASM; PATHOLOGY;

EUKARYOTA;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANIMALS; CELL GROWTH PROCESSES; HUMANS; NEOPLASMS; PROTEIN KINASES; RAS PROTEINS; SIGNAL TRANSDUCTION;

EID: 33745307617     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/nature04869     Document Type: Review

References (84)

1. McCormick, F. Signalling networks that cause cancer. Trends Cell. Biol. 9, M53-M56 (1999).
2. Luo, J., Manning, B. D. & Cantley, L. C. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4, 257-262 (2003).
3. Bader, A. G., Kang, S., Zhao, L. & Vogt, P. K. Oncogenic PI3K deregulates transcription and translation. Nature Rev. Cancer 5, 921-929 (2005).
4. Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471-484 (2006).
5. Garnett, M. J. & Marais, R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6, 313-319 (2004).
6. Garnett, M. J., Rana, S., Paterson, H., Barford, D. & Marais, R. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol. Cell 20, 963-969 (2005).
7. Rodriguez-Viciana, P., Sabatier, C. & McCormick, F. Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Mol. Cell. Biol. 24, 4943-4954 (2004).
8. Cichowski, K. & Jacks, T. NF1 tumor suppressor gene function: narrowing the GAP. Cell 104, 593-604 (2001).
9. Kolfschoten, I. G. et al. A genetic screen identifies PITX1 as a suppressor of RAS activity and tumorigenicity. Cell 121, 849-858 (2005).
10. Johnson, S. M. et al. RAS is regulated by the let-7 microRNA family. Cell 120, 635-647 (2005).
11. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).
12. Samuels, Y. et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7, 561-573 (2005).
13. Parsons, D. W. et al. Colorectal cancer: mutations in a signalling pathway. Nature 436, 792 (2005).
14. Teitell, M. A. The TCL1 family of oncoproteins: co-activators of transformation. Nature Rev. Cancer 5, 640-648 (2005).
15. 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).
16. 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).
17. Gao, T., Furnari, F. & Newton, A. C. PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol. Cell 18, 13-24 (2005).
18. Frame, S. & Cohen, P. GSK3 takes centre stage more than 20 years after its discovery. Biochem. J. 359, 1-16 (2001).
19. Fbw7. Cell Cycle 4, 1356-1359 (2005).
20. 2/M cell cycle checkpoint induced by DNA damage. Mol. Cell. Biol. 22, 7831-7841 (2002).
21. Lee, C., Kim, J. S. & Waldman, T. PTEN gene targeting reveals a radiation-induced size checkpoint in human cancer cells. Cancer Res. 64, 6906-6914 (2004).
22. Puc, J. et al. Lack of PTEN sequesters CHK1 and initiates genetic instability. Cancer Cell 7, 193-204 (2005).
23. Mayo, L. D. & Donner, D. B. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem. Sci. 27, 462-467 (2002).
24. Datta, S. R. et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231-241 (1997).
25. del Peso, L., Gonzalez-Garcia, M., Page, C., Herrera, R. & Nunez, G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278, 687-689 (1997).
26. Accili, D. & Arden, K. C. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117, 421-426 (2004).
27. So, C. W. & Cleary, M. L. Common mechanism for oncogenic activation of MLL by forkhead family proteins. Blood 101, 633-639 (2003).
28. Manning, B. D. & Cantley, L. C. United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem. Soc. Trans. 31, 573-578 (2003).
29. Hammerman, P. S., Fox, C. J. & Thompson, C. B. Beginnings of a signal-transduction pathway for bioenergetic control of cell survival. Trends Biochem. Sci. 29, 586-592 (2004).
30. 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).
31. Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296-1302 (2004).
32. Hresko, R. C. & Mueckler, M. mTOR/RICTOR is the Ser473 kinase for Akt/PKB in 3T3-L1 adipocytes. J. Biol. Chem. 280, 40406-40416 (2005).
33. Lee, S. et al. TOR complex 2 integrates cell movement during chemotaxis and signal relay in Dictyostelium. Mol. Biol. Cell 16, 4572-4583 (2005).
34. Ballif, B. A. et al. Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors. Proc. Natl Acad. Sci. USA 102, 667-672 (2005).
35. Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P. & Pandolfi, P. P. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179-193 (2005).
36. Roux, P. P., Ballif, B. A., Anjum, R., Gygi, S. P. & Blenis, J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl Acad. Sci. USA 101, 13489-13494 (2004).
37. Johannessen, C. M. et al. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl Acad. Sci. USA 102, 8573-8578 (2005).
38. Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391, 184-187 (1998).
39. Sanchez-Cespedes, M. et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 62, 3659-3662 (2002).
40. Hawley, S. A. et al. Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2, 28 (2003).
41. Woods, A. et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004-2008 (2003).
42. Shaw, R. J. et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl Acad. Sci. USA 101, 3329-3335 (2004).
43. Hardie, D. G. New roles for the LKB1-AMPK pathway. Curr. Opin. Cell Biol. 17, 167-173 (2005).
44. Corradetti, M. N., Inoki, K., Bardeesy, N., DePinho, R. A. & Guan, K. L. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev. 18, 1533-1538 (2004).
45. Shaw, R. J. et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91-99 (2004).
46. Shaw, R. J. et al. Deletion of the LKB1 kinase in liver impairs AMPK activation, glucose homeostasis, and therapeutic effects of metformin. Science 310, 1642-1646 (2005).
47. Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577-590 (2003).
48. Liu, L. et al. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol. Cell 21, 521-531 (2006).
49. Dougherty, M. K. et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol. Cell 17, 215-224 (2005).
50. Macrae, M. et al. A conditional feedback loop regulates Ras activity through EphA2 Cancer Cell 8, 111-118 (2005).
51. Manning, B. D. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J. Cell Biol. 167, 399-403 (2004).
52. Harrington, L. S. et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol. 166, 213-223 (2004).
53. Radimerski, T., Montagne, J., Hemmings-Mieszczak, M. & Thomas, G. Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling. Genes Dev. 16, 2627-2632 (2002).
54. Shah, O. J., Wang, Z. & Hunter, T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol. 14, 1650-1656 (2004).
55. Um, S. H. et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200-205 (2004).
56. Manning, B. D. et al. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev. 19, 1773-1778 (2005).
57. Zhang, H. et al. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J. Clin. Invest. 112, 1223-1233 (2003).
58. Hay, N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 8, 179-183 (2005).
59. Granville, C. A., Memmott, R. M., Gills, J. J. & Dennis, P. A. Handicapping the race to develop inhibitors of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway. Clin. Cancer Res. 12, 679-689 (2006).
60. Sun, S. Y. et al. Activation of Akt and elF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 65, 7052-7058 (2005).
61. O'Reilly, K. E. et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 1500-1508 (2006).
62. Wendel, H. G. et al. Survival signalling by Akt and elF4E in oncogenesis and cancer therapy. Nature 428, 332-337 (2004).
63. 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).
64. To, M. D., Perez-Losada, J., Mao, J. H. & Balmain, A. Crosstalk between Pten and Ras signaling pathways in tumor development. Cell Cycle 4, 1185-1188 (2005).
65. Daniotti, M. et al. BRAF alterations are associated with complex mutational profiles in malignant melanoma. Oncogene 23, 5968-5977 (2004).
66. Tsao, H., Goel, V., Wu, H., Yang, G. & Haluska, F. G. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. J. Invest. Dermatol. 122, 337-341 (2004).
67. She, Q. B. et al. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 8, 287-297 (2005).
68. Ding, Q. et al. Erk associates with and primes GSK-3β for its inactivation resulting in upregulation of β-catenin. Mol. Cell 19, 159-170 (2005).
69. Roux, P. P. & Blenis, J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol. Mol. Biol. Rev. 68, 320-344 (2004).
70. Culler, P. J. Ras effectors: buying shares in Ras plc. Curr. Biol. 11, R342-R344 (2001).
71. Lambert, J. M. et al. Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nature Cell Biol. 4, 621-625 (2002).
72. Gonzalez-Garcia, A. et al. RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell 7, 219-226 (2005).
73. Bai, Y. et al. Crucial role of phospholipase Cε in chemical carcinogen-induced skin tumor development. Cancer Res. 64, 8808-8810 (2004).
74. Malliri, A. et al. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417, 867-871 (2002).
75. 3 binding to PDK1 PH domain defined by knockin mutation. EMBO J. 23, 2071-2082 (2004).
76. Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K. & Avruch, J. Rheb binds and regulates the mTOR kinase. Curr. Biol. 15, 702-713 (2005).
77. Smith, E. M., Finn, S. G., Tee, A. R., Browne, G. J. & Proud, C. G. The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J. Biol. Chem. 280, 18717-18727 (2005).
78. Hahn-Windgassen, A. et al. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J. Biol. Chem. 280, 32081-32089 (2005).
79. Horman, S. et al. Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase α-subunits in heart via hierarchical phosphorylation of Ser485/491. J. Biol. Chem. 281, 5335-5340 (2006).
80. Holz, M. K., Ballif, B. A., Gygi, S. P. & Blenis, J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123, 569-580 (2005).
81. Fingar, D. C. & Blenis, J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23, 3151-3171 (2004).
82. Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 18, 1926-1945 (2004).
83. Kim, W. Y. & Kaelin, W. G. Role of VHL gene mutation in human cancer. J. Clin. Oncol. 22, 4991-5004 (2004).
84. Thomas, G. V. et al. Hypoxia-inducible facor determines sensitivity to inhibitors of mTOR in kidney cancer. Nature Med. 12, 122-127 (2006).