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Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKB

Sarbassov, Dos D., Ali, Siraj M., Sengupta, Shomit, Sheen, Joon-Ho, Hsu, Peggy P., Bagley, Alex F., Markhard, Andrew L., Sabatini, David M.·2006·Molecular Cell
DOI 10.1016/j.molcel.2006.03.029
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Abstract

The drug rapamycin has important uses in oncology, cardiology, and transplantation medicine, but its clinically relevant molecular effects are not understood. When bound to FKBP12, rapamycin interacts with and inhibits the kinase activity of a multiprotein complex composed of mTOR, mLST8, and raptor (mTORC1). The distinct complex of mTOR, mLST8, and rictor (mTORC2) does not interact with FKBP12-rapamycin and is not thought to be rapamycin sensitive. mTORC2 phosphorylates and activates Akt/PKB, a key regulator of cell survival. Here we show that rapamycin inhibits the assembly of mTORC2 and that, in many cell types, prolonged rapamycin treatment reduces the levels of mTORC2 below those needed to maintain Akt/PKB signaling. The proapoptotic and antitumor effects of rapamycin are suppressed in cells expressing an Akt/PKB mutant that is rapamycin resistant. Our work describes an unforeseen mechanism of action for rapamycin that suggests it can be used to inhibit Akt/PKB in certain cell types.

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  • mTORC2 is inhibited in cell culture and in vivo in mice when exposed to high concentrations of rapamycin for a prolonged period, most likely due to sequestration of free mTOR by rapamycin.

    “Although mTORC2 is not acutely inhibited by rapamycin, subsequent studies have shown that mTORC2 is inhibited in cell culture as well as in vivo in mice when exposed to high concentrations of rapamycin for a prolonged period of time, most likely due to the sequestration of free of mTOR by rapamycin so that it is unavailable for incorporation into mTORC2 17,32”

    From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [32]

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Research works printed but not linked: 41

  1. Alessi, 1996, Mechanism of activation of protein kinase B by insulin and IGF-1, EMBO J., 15, 6541, 10.1002/j.1460-2075.1996.tb01045.x · DOI
  2. Ali, 2005, Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site, J. Biol. Chem., 280, 19445, 10.1074/jbc.C500125200 · DOI
  3. Brown, 1994, A mammalian protein targeted by G1-arresting rapamycin-receptor complex, Nature, 369, 756, 10.1038/369756a0 · DOI · Paper page
  4. Brunet, 1999, Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor, Cell, 96, 857, 10.1016/S0092-8674(00)80595-4 · DOI
  5. Burnett, 1998, RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1, Proc. Natl. Acad. Sci. USA, 95, 1432, 10.1073/pnas.95.4.1432 · DOI
  6. Chinni, 2002, Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells, Clin. Cancer Res., 8, 1228
  7. Chueh, 2005, Clinical application of sirolimus in renal transplantation: an update, Transpl. Int., 18, 261, 10.1111/j.1432-2277.2004.00039.x · DOI
  8. del Peso, 1999, Regulation of the forkhead transcription factor FKHR, but not the PAX3-FKHR fusion protein, by the serine/threonine kinase Akt, Oncogene, 18, 7328, 10.1038/sj.onc.1203159 · DOI
  9. Di Mario, 2004, The impact of Sirolimus Eluting stents in interventional cardiology, Int. J. Cardiol., 95, 117, 10.1016/j.ijcard.2003.10.010 · DOI
  10. Edinger, 2003, Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells, Cancer Res., 63, 8451
  11. Elks, 1985, Antilipolytic action of insulin: role of cAMP phosphodiesterase activation, Endocrinology, 116, 2119, 10.1210/endo-116-5-2119 · DOI
  12. Frost, 1985, Evidence for the involvement of vicinal sulfhydryl groups in insulin-activated hexose transport by 3T3-L1 adipocytes, J. Biol. Chem., 260, 2646, 10.1016/S0021-9258(18)89409-1 · DOI
  13. Guba, 2002, Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor, Nat. Med., 8, 128, 10.1038/nm0202-128 · DOI
  14. Guertin, 2005, An expanding role for mTOR in cancer, Trends Mol. Med., 11, 353, 10.1016/j.molmed.2005.06.007 · DOI
  15. Harrington, 2004, The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins, J. Cell Biol., 166, 213, 10.1083/jcb.200403069 · DOI
  16. Hresko, 2005, mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes, J. Biol. Chem., 280, 40406, 10.1074/jbc.M508361200 · DOI
  17. Jacinto, 2004, Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive, Nat. Cell Biol., 6, 1122, 10.1038/ncb1183 · DOI
  18. Kane, 2003, The PI-3 kinase/Akt pathway and T cell activation: pleiotropic pathways downstream of PIP3, Immunol. Rev., 192, 7, 10.1034/j.1600-065X.2003.00008.x · DOI
  19. Kim, 2002, mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery, Cell, 110, 163, 10.1016/S0092-8674(02)00808-5 · DOI
  20. Kops, 1999, Direct control of the Forkhead transcription factor AFX by protein kinase B, Nature, 398, 630, 10.1038/19328 · DOI
  21. Lawlor, 2002, Essential role of PDK1 in regulating cell size and development in mice, EMBO J., 21, 3728, 10.1093/emboj/cdf387 · DOI
  22. Lee, 2004, PTEN gene targeting reveals a radiation-induced size checkpoint in human cancer cells, Cancer Res., 64, 6906, 10.1158/0008-5472.CAN-04-1767 · DOI
  23. Morrisett, 2003, Sirolimus changes lipid concentrations and lipoprotein metabolism in kidney transplant recipients, Transplant. Proc., 35, 143S, 10.1016/S0041-1345(03)00233-1 · DOI
  24. Neshat, 2001, Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR, Proc. Natl. Acad. Sci. USA, 98, 10314, 10.1073/pnas.171076798 · DOI
  25. O'Reilly, 2006, mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt, Cancer Res., 66, 1500, 10.1158/0008-5472.CAN-05-2925 · DOI · Paper page
  26. Panwalkar, 2004, Mammalian target of rapamycin inhibition as therapy for hematologic malignancies, Cancer, 100, 657, 10.1002/cncr.20026 · DOI
  27. Podsypanina, 2001, An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice, Proc. Natl. Acad. Sci. USA, 98, 10320, 10.1073/pnas.171060098 · DOI
  28. Rena, 2002, Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion, EMBO J., 21, 2263, 10.1093/emboj/21.9.2263 · DOI
  29. Sabatini, 1994, RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs, Cell, 78, 35, 10.1016/0092-8674(94)90570-3 · DOI · Paper page
  30. Sarbassov, 2004, Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton, Curr. Biol., 14, 1296, 10.1016/j.cub.2004.06.054 · DOI · Paper page
  31. Sarbassov, 2005, Growing roles for the mTOR pathway, Curr. Opin. Cell Biol., 17, 596, 10.1016/j.ceb.2005.09.009 · DOI
  32. Sawyers, 2003, Will mTOR inhibitors make it as cancer drugs?, Cancer Cell, 4, 343, 10.1016/S1535-6108(03)00275-7 · DOI
  33. Scheid, 2003, Unravelling the activation mechanisms of protein kinase B/Akt, FEBS Lett., 546, 108, 10.1016/S0014-5793(03)00562-3 · DOI
  34. Scheid, 2002, Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B, Mol. Cell. Biol., 22, 6247, 10.1128/MCB.22.17.6247-6260.2002 · DOI
  35. Takaishi, 1999, Regulation of nuclear translocation of forkhead transcription factor AFX by protein kinase B, Proc. Natl. Acad. Sci. USA, 96, 11836, 10.1073/pnas.96.21.11836 · DOI
  36. Tang, 1999, Negative regulation of the forkhead transcription factor FKHR by Akt, J. Biol. Chem., 274, 16741, 10.1074/jbc.274.24.16741 · DOI
  37. Tremblay, 2001, Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells, J. Biol. Chem., 276, 38052, 10.1074/jbc.M106703200 · DOI
  38. Wijkander, 1998, Insulin-induced phosphorylation and activation of phosphodiesterase 3B in rat adipocytes: possible role for protein kinase B but not mitogen-activated protein kinase or p70 S6 kinase, Endocrinology, 139, 219, 10.1210/endo.139.1.5693 · DOI
  39. Xu, 2002, The inducible expression of the tumor suppressor gene PTEN promotes apoptosis and decreases cell size by inhibiting the PI3K/Akt pathway in Jurkat T cells, Cell Growth Differ., 13, 285
  40. Yang, 2002, Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation, Mol. Cell, 9, 1227, 10.1016/S1097-2765(02)00550-6 · DOI
  41. Zhou, 2003, Stent implantation activates Akt in the vessel wall: role of mechanical stretch in vascular smooth muscle cells, Arterioscler. Thromb. Vasc. Biol., 23, 2015, 10.1161/01.ATV.0000095161.06906.ED · DOI

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Metadata

Authors
Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J.-H., Hsu, P. P., Bagley, A. F., Markhard, A. L., & Sabatini, D. M.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2006-04
Volume
22
Issue
2
Pages
159-168
ISSN
1097-2765
DOI
10.1016/j.molcel.2006.03.029
Cited by
2,365
References
4
Language
en
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