This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sekulic, A. Articles by Abraham, R. T. Search for Related Content PubMed PubMed Citation Articles by Sekulic, A. Articles by Abraham, R. T.

A Direct Linkage between the Phosphoinositide 3-Kinase-AKT Signaling Pathway and the Mammalian Target of Rapamycin in Mitogen-stimulated and Transformed Cells¹

Aleksandar Sekuli², Christine C. Hudson², James L. Homme, Peng Yin, Diane M. Otterness, Larry M. Karnitz and Robert T. Abraham³

Department of Immunology [A. S.], Mayo School of Medicine [J. L. H.], and Division of Oncology Research [L. M. K.], Mayo Clinic, Rochester, Minnesota 55905, and Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 [C. C. H., P. Y., D. M. O., R. T. A.]

The microbially derived antiproliferative agent rapamycin inhibits cell growth by interfering with the signaling functions of the mammalian target of rapamycin (mTOR). In this study, we demonstrate that interleukin-3 stimulation induces a wortmannin-sensitive increase in mTOR kinase activity in a myeloid progenitor cell line. The involvement of phosphoinositide 3'-kinase (PI3K) in the regulation of mTOR activity was further suggested by findings that mTOR was phosphorylated in vitro and in vivo by the PI3K-regulated protein kinase, AKT/PKB. Although AKT phosphorylated mTOR at two COOH-terminal sites (Thr²⁴⁴⁶ and Ser²⁴⁴⁸) in vitro, Ser²⁴⁴⁸ was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. Transient transfection assays with mTOR mutants bearing Ala substitutions at Ser²⁴⁴⁸ and/or Thr²⁴⁴⁶ indicated that AKT-dependent mTOR phosphorylation was not essential for either PHAS-I phosphorylation or p70^S6K activation in HEK cells. However, a deletion of amino acids 2430–2450 in mTOR, which includes the potential AKT phosphorylation sites, significantly increased both the basal protein kinase activity and in vivo signaling functions of mTOR. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a "repressor domain" that negatively regulates the catalytic activity of mTOR. Furthermore, the activation status of the PI3K-AKT pathway in cancer cells may be an important determinant of cellular sensitivity to the cytostatic effect of rapamycin.

This article has been cited by other articles:

				A. Chale-Rush, E. P. Morris, T. L. Kendall, N. E. Brooks, and R. A. Fielding Effects of Chronic Overload on Muscle Hypertrophy and mTOR Signaling in Young Adult and Aged Rats J Gerontol A Biol Sci Med Sci, December 1, 2009; 64A(12): 1232 - 1239. [Abstract] [Full Text] [PDF]

				G. Panasyuk, I. Nemazanyy, A. Zhyvoloup, V. Filonenko, D. Davies, M. Robson, R. B. Pedley, M. Waterfield, and I. Gout mTOR{beta} Splicing Isoform Promotes Cell Proliferation and Tumorigenesis J. Biol. Chem., November 6, 2009; 284(45): 30807 - 30814. [Abstract] [Full Text] [PDF]

				A. Belfiore, F. Frasca, G. Pandini, L. Sciacca, and R. Vigneri Insulin Receptor Isoforms and Insulin Receptor/Insulin-Like Growth Factor Receptor Hybrids in Physiology and Disease Endocr. Rev., October 1, 2009; 30(6): 586 - 623. [Abstract] [Full Text] [PDF]

				S. L. Ellard, M. Clemons, K. A. Gelmon, B. Norris, H. Kennecke, S. Chia, K. Pritchard, A. Eisen, T. Vandenberg, M. Taylor, et al. Randomized Phase II Study Comparing Two Schedules of Everolimus in Patients With Recurrent/Metastatic Breast Cancer: NCIC Clinical Trials Group IND.163 J. Clin. Oncol., September 20, 2009; 27(27): 4536 - 4541. [Abstract] [Full Text] [PDF]

				H. A. Acosta-Jaquez, J. A. Keller, K. G. Foster, B. Ekim, G. A. Soliman, E. P. Feener, B. A. Ballif, and D. C. Fingar Site-Specific mTOR Phosphorylation Promotes mTORC1-Mediated Signaling and Cell Growth Mol. Cell. Biol., August 1, 2009; 29(15): 4308 - 4324. [Abstract] [Full Text] [PDF]

				N. Nitin, W. J. Rhee, and G. Bao Translation inhibition reveals interaction of 2'-deoxy and 2'-O-methyl molecular beacons with mRNA targets in living cells Nucleic Acids Res., August 1, 2009; 37(15): 4977 - 4986. [Abstract] [Full Text] [PDF]

				J. I. Baum, S. R. Kimball, and L. S. Jefferson Glucagon acts in a dominant manner to repress insulin-induced mammalian target of rapamycin complex 1 signaling in perfused rat liver Am J Physiol Endocrinol Metab, August 1, 2009; 297(2): E410 - E415. [Abstract] [Full Text] [PDF]

				M. El-Salem, P. N. Raghunath, M. Marzec, X. Liu, M. Kasprzycka, E. Robertson, and M. A. Wasik Activation of mTORC1 Signaling Pathway in AIDS-Related Lymphomas Am. J. Pathol., August 1, 2009; 175(2): 817 - 824. [Abstract] [Full Text] [PDF]

				W. A. Tyler, N. Gangoli, P. Gokina, H. A. Kim, M. Covey, S. W. Levison, and T. L. Wood Activation of the Mammalian Target of Rapamycin (mTOR) Is Essential for Oligodendrocyte Differentiation J. Neurosci., May 13, 2009; 29(19): 6367 - 6378. [Abstract] [Full Text] [PDF]

				J. Copp, G. Manning, and T. Hunter TORC-Specific Phosphorylation of Mammalian Target of Rapamycin (mTOR): Phospho-Ser2481 Is a Marker for Intact mTOR Signaling Complex 2 Cancer Res., March 1, 2009; 69(5): 1821 - 1827. [Abstract] [Full Text] [PDF]

				J. P. Gustin, B. Karakas, M. B. Weiss, A. M. Abukhdeir, J. Lauring, J. P. Garay, D. Cosgrove, A. Tamaki, H. Konishi, Y. Konishi, et al. Knockin of mutant PIK3CA activates multiple oncogenic pathways PNAS, February 24, 2009; 106(8): 2835 - 2840. [Abstract] [Full Text] [PDF]

				P. Giussani, L. Brioschi, R. Bassi, L. Riboni, and P. Viani Phosphatidylinositol 3-Kinase/AKT Pathway Regulates the Endoplasmic Reticulum to Golgi Traffic of Ceramide in Glioma Cells: A LINK BETWEEN LIPID SIGNALING PATHWAYS INVOLVED IN THE CONTROL OF CELL SURVIVAL J. Biol. Chem., February 20, 2009; 284(8): 5088 - 5096. [Abstract] [Full Text] [PDF]

				W. Zhu, M. H. Soonpaa, H. Chen, W. Shen, R. M. Payne, E. A. Liechty, R. L. Caldwell, W. Shou, and L. J. Field Acute Doxorubicin Cardiotoxicity Is Associated With p53-Induced Inhibition of the Mammalian Target of Rapamycin Pathway Circulation, January 6, 2009; 119(1): 99 - 106. [Abstract] [Full Text] [PDF]

				A. Amirouche, A.-C. Durieux, S. Banzet, N. Koulmann, R. Bonnefoy, C. Mouret, X. Bigard, A. Peinnequin, and D. Freyssenet Down-Regulation of Akt/Mammalian Target of Rapamycin Signaling Pathway in Response to Myostatin Overexpression in Skeletal Muscle Endocrinology, January 1, 2009; 150(1): 286 - 294. [Abstract] [Full Text] [PDF]

				T Weichhart and M D Saemann The PI3K/Akt/mTOR pathway in innate immune cells: emerging therapeutic applications Ann Rheum Dis, December 1, 2008; 67(Suppl_3): iii70 - iii74. [Abstract] [Full Text] [PDF]

				A. M. Miller, J. R. Brestoff, C. B. Phelps, E. Z. Berk, and T. H. Reynolds IV Rapamycin does not improve insulin sensitivity despite elevated mammalian target of rapamycin complex 1 activity in muscles of ob/ob mice Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2008; 295(5): R1431 - R1438. [Abstract] [Full Text] [PDF]

				H.-w. Yung, S. Calabrese, D. Hynx, B. A. Hemmings, I. Cetin, D. S. Charnock-Jones, and G. J. Burton Evidence of Placental Translation Inhibition and Endoplasmic Reticulum Stress in the Etiology of Human Intrauterine Growth Restriction Am. J. Pathol., August 1, 2008; 173(2): 451 - 462. [Abstract] [Full Text] [PDF]

				L. Yang, M. J. Clarke, B. L. Carlson, A. C. Mladek, M. A. Schroeder, P. Decker, W. Wu, G. J. Kitange, P. T. Grogan, J. M. Goble, et al. PTEN Loss Does Not Predict for Response to RAD001 (Everolimus) in a Glioblastoma Orthotopic Xenograft Test Panel Clin. Cancer Res., June 15, 2008; 14(12): 3993 - 4001. [Abstract] [Full Text] [PDF]

				D. A. Mordes, G. G. Glick, R. Zhao, and D. Cortez TopBP1 activates ATR through ATRIP and a PIKK regulatory domain Genes & Dev., June 1, 2008; 22(11): 1478 - 1489. [Abstract] [Full Text] [PDF]

				W.-H. Shen, Z. Chen, S. Shi, H. Chen, W. Zhu, A. Penner, G. Bu, W. Li, D. W. Boyle, M. Rubart, et al. Cardiac Restricted Overexpression of Kinase-dead Mammalian Target of Rapamycin (mTOR) Mutant Impairs the mTOR-mediated Signaling and Cardiac Function J. Biol. Chem., May 16, 2008; 283(20): 13842 - 13849. [Abstract] [Full Text] [PDF]

				M. Fraenkel, M. Ketzinel-Gilad, Y. Ariav, O. Pappo, M. Karaca, J. Castel, M.-F. Berthault, C. Magnan, E. Cerasi, N. Kaiser, et al. mTOR Inhibition by Rapamycin Prevents {beta}-Cell Adaptation to Hyperglycemia and Exacerbates the Metabolic State in Type 2 Diabetes Diabetes, April 1, 2008; 57(4): 945 - 957. [Abstract] [Full Text] [PDF]

				P. Jiang, A. Enomoto, M. Jijiwa, T. Kato, T. Hasegawa, M. Ishida, T. Sato, N. Asai, Y. Murakumo, and M. Takahashi An Actin-Binding Protein Girdin Regulates the Motility of Breast Cancer Cells Cancer Res., March 1, 2008; 68(5): 1310 - 1318. [Abstract] [Full Text] [PDF]

				D. M. Thomson, C. A. Fick, and S. E. Gordon AMPK activation attenuates S6K1, 4E-BP1, and eEF2 signaling responses to high-frequency electrically stimulated skeletal muscle contractions J Appl Physiol, March 1, 2008; 104(3): 625 - 632. [Abstract] [Full Text] [PDF]

				T. Miyamoto, N. Oshiro, K.-i. Yoshino, A. Nakashima, S. Eguchi, M. Takahashi, Y. Ono, U. Kikkawa, and K. Yonezawa AMP-activated Protein Kinase Phosphorylates Golgi-specific Brefeldin A Resistance Factor 1 at Thr1337 to Induce Disassembly of Golgi Apparatus J. Biol. Chem., February 15, 2008; 283(7): 4430 - 4438. [Abstract] [Full Text] [PDF]

				M. Marzec, X. Liu, M. Kasprzycka, A. Witkiewicz, P. N. Raghunath, M. El-Salem, E. Robertson, N. Odum, and M. A. Wasik IL-2- and IL-15-induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes Blood, February 15, 2008; 111(4): 2181 - 2189. [Abstract] [Full Text] [PDF]

				A. Yaba, V. Bianchi, A. Borini, and J. Johnson A Putative Mitotic Checkpoint Dependent on mTOR Function Controls Cell Proliferation and Survival in Ovarian Granulosa Cells Reproductive Sciences, February 1, 2008; 15(2): 128 - 138. [Abstract] [PDF]

				F. C. Harwood, L. Shu, and P. J. Houghton mTORC1 Signaling Can Regulate Growth Factor Activation of p44/42 Mitogen-activated Protein Kinases through Protein Phosphatase 2A J. Biol. Chem., February 1, 2008; 283(5): 2575 - 2585. [Abstract] [Full Text] [PDF]

				T. Hayashi, M. Hatanaka, K. Nagao, Y. Nakaseko, J. Kanoh, A. Kokubu, M. Ebe, and M. Yanagida Rapamycin sensitivity of the Schizosaccharomyces pombe tor2 mutant and organization of two highly phosphorylated TOR complexes by specific and common subunits. Genes Cells, December 1, 2007; 12(12): 1357 - 1370. [Abstract] [Full Text] [PDF]

				H. Jin, S.-H. Chang, C.-X. Xu, J.-Y. Shin, Y.-S. Chung, S.-J. Park, Y.-S. Lee, G.-H. An, K.-H. Lee, and M.-H. Cho High Dietary Inorganic Phosphate Affects Lung through Altering Protein Translation, Cell Cycle, and Angiogenesis in Developing Mice Toxicol. Sci., November 1, 2007; 100(1): 215 - 223. [Abstract] [Full Text] [PDF]

				L. Wang, T. E. Harris, R. A. Roth, and J. C. Lawrence Jr PRAS40 Regulates mTORC1 Kinase Activity by Functioning as a Direct Inhibitor of Substrate Binding J. Biol. Chem., July 6, 2007; 282(27): 20036 - 20044. [Abstract] [Full Text] [PDF]

				A. Tzatsos and P. N. Tsichlis Energy Depletion Inhibits Phosphatidylinositol 3-Kinase/Akt Signaling and Induces Apoptosis via AMP-activated Protein Kinase-dependent Phosphorylation of IRS-1 at Ser-794 J. Biol. Chem., June 22, 2007; 282(25): 18069 - 18082. [Abstract] [Full Text] [PDF]

				P. Tsokas, T. Ma, R. Iyengar, E. M. Landau, and R. D. Blitzer Mitogen-Activated Protein Kinase Upregulates the Dendritic Translation Machinery in Long-Term Potentiation by Controlling the Mammalian Target of Rapamycin Pathway J. Neurosci., May 30, 2007; 27(22): 5885 - 5894. [Abstract] [Full Text] [PDF]

				R. Parent, D. Kolippakkam, G. Booth, and L. Beretta Mammalian Target of Rapamycin Activation Impairs Hepatocytic Differentiation and Targets Genes Moderating Lipid Homeostasis and Hepatocellular Growth Cancer Res., May 1, 2007; 67(9): 4337 - 4345. [Abstract] [Full Text] [PDF]

				N. Lehman, B. Ledford, M. Di Fulvio, K. Frondorf, L. C. McPhail, and J. Gomez-Cambronero Phospholipase D2-derived phosphatidic acid binds to and activates ribosomal p70 S6 kinase independently of mTOR FASEB J, April 1, 2007; 21(4): 1075 - 1087. [Abstract] [Full Text] [PDF]

				J. Cruz, A Ocana, E Del Barco, and A Pandiella Targeting receptor tyrosine kinases and their signal transduction routes in head and neck cancer Ann. Onc., March 1, 2007; 18(3): 421 - 430. [Abstract] [Full Text] [PDF]

				J. Urano, T. Sato, T. Matsuo, Y. Otsubo, M. Yamamoto, and F. Tamanoi Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells PNAS, February 27, 2007; 104(9): 3514 - 3519. [Abstract] [Full Text] [PDF]

				V. Folgiero, R. E. Bachelder, G. Bon, A. Sacchi, R. Falcioni, and A. M. Mercurio The {alpha}6{beta}4 Integrin Can Regulate ErbB-3 Expression: Implications for {alpha}6{beta}4 Signaling and Function Cancer Res., February 15, 2007; 67(4): 1645 - 1652. [Abstract] [Full Text] [PDF]

				L. Leseux, S. M. Hamdi, T. al Saati, F. Capilla, C. Recher, G. Laurent, and C. Bezombes Syk-dependent mTOR activation in follicular lymphoma cells Blood, December 15, 2006; 108(13): 4156 - 4162. [Abstract] [Full Text] [PDF]

				T. Inoue, T. Yoshida, Y. Shimizu, T. Kobayashi, T. Yamasaki, Y. Toda, T. Segawa, T. Kamoto, E. Nakamura, and O. Ogawa Requirement of Androgen-Dependent Activation of Protein Kinase C{zeta} for Androgen-Dependent Cell Proliferation in LNCaP Cells and Its Roles in Transition to Androgen-Independent Cells Mol. Endocrinol., December 1, 2006; 20(12): 3053 - 3069. [Abstract] [Full Text] [PDF]

				M. Jankiewicz, B. Groner, and S. Desrivieres Mammalian Target of Rapamycin Regulates the Growth of Mammary Epithelial Cells through the Inhibitor of Deoxyribonucleic Acid Binding Id1 and Their Functional Differentiation through Id2 Mol. Endocrinol., October 1, 2006; 20(10): 2369 - 2381. [Abstract] [Full Text] [PDF]

				M. Hidalgo, J. C. Buckner, C. Erlichman, M. S. Pollack, J. P. Boni, G. Dukart, B. Marshall, L. Speicher, L. Moore, and E. K. Rowinsky A Phase I and Pharmacokinetic Study of Temsirolimus (CCI-779) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients with Advanced Cancer. Clin. Cancer Res., October 1, 2006; 12(19): 5755 - 5763. [Abstract] [Full Text] [PDF]

				A. Suryawan, J. Escobar, J. W. Frank, H. V. Nguyen, and T. A. Davis Developmental regulation of the activation of signaling components leading to translation initiation in skeletal muscle of neonatal pigs Am J Physiol Endocrinol Metab, October 1, 2006; 291(4): E849 - E859. [Abstract] [Full Text] [PDF]

				T. C. Vary and C. J. Lynch Meal Feeding Stimulates Phosphorylation of Multiple Effector Proteins Regulating Protein Synthetic Processes in Rat Hearts J. Nutr., September 1, 2006; 136(9): 2284 - 2290. [Abstract] [Full Text] [PDF]

				L. Wang, C. J. Rhodes, and J. C. Lawrence Jr. Activation of Mammalian Target of Rapamycin (mTOR) by Insulin Is Associated with Stimulation of 4EBP1 Binding to Dimeric mTOR Complex 1 J. Biol. Chem., August 25, 2006; 281(34): 24293 - 24303. [Abstract] [Full Text] [PDF]

				P. K. Dash, S. A. Orsi, and A. N. Moore Spatial Memory Formation and Memory-Enhancing Effect of Glucose Involves Activation of the Tuberous Sclerosis Complex-Mammalian Target of Rapamycin Pathway J. Neurosci., August 2, 2006; 26(31): 8048 - 8056. [Abstract] [Full Text] [PDF]

				A. Charest, E. W. Wilker, M. E. McLaughlin, K. Lane, R. Gowda, S. Coven, K. McMahon, S. Kovach, Y. Feng, M. B. Yaffe, et al. ROS Fusion Tyrosine Kinase Activates a SH2 Domain-Containing Phosphatase-2/Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Signaling Axis to Form Glioblastoma in Mice. Cancer Res., August 1, 2006; 66(15): 7473 - 7481. [Abstract] [Full Text] [PDF]

				F. Vega, L. J. Medeiros, V. Leventaki, C. Atwell, J. H. Cho-Vega, L. Tian, F.-X. Claret, and G. Z. Rassidakis Activation of Mammalian Target of Rapamycin Signaling Pathway Contributes to Tumor Cell Survival in Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma. Cancer Res., July 1, 2006; 66(13): 6589 - 6597. [Abstract] [Full Text] [PDF]

				D. M. Thomson and S. E. Gordon Impaired overload-induced muscle growth is associated with diminished translational signalling in aged rat fast-twitch skeletal muscle J. Physiol., July 1, 2006; 574(1): 291 - 305. [Abstract] [Full Text] [PDF]

				M. I. Lewis, S. C. Bodine, N. Kamangar, X. Xu, X. Da, and M. Fournier Effect of severe short-term malnutrition on diaphragm muscle signal transduction pathways influencing protein turnover J Appl Physiol, June 1, 2006; 100(6): 1799 - 1806. [Abstract] [Full Text] [PDF]

				E. Connolly, S. Braunstein, S. Formenti, and R. J. Schneider Hypoxia Inhibits Protein Synthesis through a 4E-BP1 and Elongation Factor 2 Kinase Pathway Controlled by mTOR and Uncoupled in Breast Cancer Cells Mol. Cell. Biol., May 15, 2006; 26(10): 3955 - 3965. [Abstract] [Full Text] [PDF]

				H. Ito, H. Aoki, F. Kuhnel, Y. Kondo, S. Kubicka, T. Wirth, E. Iwado, A. Iwamaru, K. Fujiwara, K. R. Hess, et al. Autophagic cell death of malignant glioma cells induced by a conditionally replicating adenovirus. J Natl Cancer Inst, May 3, 2006; 98(9): 625 - 636. [Abstract] [Full Text] [PDF]

				I. Yamaoka, M. Doi, M. Nakayama, A. Ozeki, S. Mochizuki, K. Sugahara, and F. Yoshizawa Intravenous administration of amino acids during anesthesia stimulates muscle protein synthesis and heat accumulation in the body Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E882 - E888. [Abstract] [Full Text] [PDF]

				T. C. Vary and C. J. Lynch Meal feeding enhances formation of eIF4F in skeletal muscle: role of increased eIF4E availability and eIF4G phosphorylation Am J Physiol Endocrinol Metab, April 1, 2006; 290(4): E631 - E642. [Abstract] [Full Text] [PDF]

				K. Funai, J. D. Parkington, S. Carambula, and R. A. Fielding Age-associated decrease in contraction-induced activation of downstream targets of Akt/mTor signaling in skeletal muscle Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2006; 290(4): R1080 - R1086. [Abstract] [Full Text] [PDF]

				K. S. Klos, S. L. Wyszomierski, M. Sun, M. Tan, X. Zhou, P. Li, W. Yang, G. Yin, W. N. Hittelman, and D. Yu ErbB2 Increases Vascular Endothelial Growth Factor Protein Synthesis via Activation of Mammalian Target of Rapamycin/p70S6K Leading to Increased Angiogenesis and Spontaneous Metastasis of Human Breast Cancer Cells Cancer Res., February 15, 2006; 66(4): 2028 - 2037. [Abstract] [Full Text] [PDF]

				F. Kaper, N. Dornhoefer, and A. J. Giaccia Mutations in the PI3K/PTEN/TSC2 Pathway Contribute to Mammalian Target of Rapamycin Activity and Increased Translation under Hypoxic Conditions Cancer Res., February 1, 2006; 66(3): 1561 - 1569. [Abstract] [Full Text] [PDF]

				R. E. Brown, P. L. Zhang, M. Lun, S. Zhu, P. K. Pellitteri, A. Law, G. C. Wood, and T. L. Kennedy Morphoproteomic and Pharmacoproteomic Rationale for mTOR Effectors as Therapeutic Targets in Head and Neck Squamous Cell Carcinoma Ann. Clin. Lab. Sci., January 1, 2006; 36(3): 273 - 282. [Abstract] [Full Text] [PDF]

				G. Ohji, S. Hidayat, A. Nakashima, C. Tokunaga, N. Oshiro, K.-i. Yoshino, K. Yokono, U. Kikkawa, and K. Yonezawa Suppression of the mTOR-Raptor Signaling Pathway by the Inhibitor of Heat Shock Protein 90 Geldanamycin J. Biochem., January 1, 2006; 139(1): 129 - 135. [Abstract] [Full Text] [PDF]

				B. J. Krawiec, R. A. Frost, T. C. Vary, L. S. Jefferson, and C. H. Lang Hindlimb casting decreases muscle mass in part by proteasome-dependent proteolysis but independent of protein synthesis Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E969 - E980. [Abstract] [Full Text] [PDF]

				P. Amornphimoltham, V. Patel, A. Sodhi, N. G. Nikitakis, J. J. Sauk, E. A. Sausville, A. A. Molinolo, and J. S. Gutkind Mammalian Target of Rapamycin, a Molecular Target in Squamous Cell Carcinomas of the Head and Neck Cancer Res., November 1, 2005; 65(21): 9953 - 9961. [Abstract] [Full Text] [PDF]

				D. J. VanderWeele and C. M. Rudin Mammalian Target of Rapamycin Promotes Vincristine Resistance through Multiple Mechanisms Independent of Maintained Glycolytic Rate Mol. Cancer Res., November 1, 2005; 3(11): 635 - 644. [Abstract] [Full Text] [PDF]

				N. Hedhli, M. Pelat, and C. Depre Protein turnover in cardiac cell growth and survival Cardiovasc Res, November 1, 2005; 68(2): 186 - 196. [Abstract] [Full Text] [PDF]

				A. Hahn-Windgassen, V. Nogueira, C.-C. Chen, J. E. Skeen, N. Sonenberg, and N. Hay Akt Activates the Mammalian Target of Rapamycin by Regulating Cellular ATP Level and AMPK Activity J. Biol. Chem., September 16, 2005; 280(37): 32081 - 32089. [Abstract] [Full Text] [PDF]

				J. Cortes and H. Kantarjian New Targeted Approaches in Chronic Myeloid Leukemia J. Clin. Oncol., September 10, 2005; 23(26): 6316 - 6324. [Abstract] [Full Text] [PDF]

				A. Creer, P. Gallagher, D. Slivka, B. Jemiolo, W. Fink, and S. Trappe Influence of muscle glycogen availability on ERK1/2 and Akt signaling after resistance exercise in human skeletal muscle J Appl Physiol, September 1, 2005; 99(3): 950 - 956. [Abstract] [Full Text] [PDF]

				P. Wlodarski, M. Kasprzycka, X. Liu, M. Marzec, E. S. Robertson, A. Slupianek, and M. A. Wasik Activation of Mammalian Target of Rapamycin in Transformed B Lymphocytes Is Nutrient Dependent but Independent of Akt, Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase, Insulin Growth Factor-I, and Serum Cancer Res., September 1, 2005; 65(17): 7800 - 7808. [Abstract] [Full Text] [PDF]

				M. K. Holz and J. Blenis Identification of S6 Kinase 1 as a Novel Mammalian Target of Rapamycin (mTOR)-phosphorylating Kinase J. Biol. Chem., July 15, 2005; 280(28): 26089 - 26093. [Abstract] [Full Text] [PDF]

				G. G. Chiang and R. T. Abraham Phosphorylation of Mammalian Target of Rapamycin (mTOR) at Ser-2448 Is Mediated by p70S6 Kinase J. Biol. Chem., July 8, 2005; 280(27): 25485 - 25490. [Abstract] [Full Text] [PDF]

				Z.-q. Yuan, D. Kim, S. Kaneko, M. Sussman, G. M. Bokoch, G. D. Kruh, S. V. Nicosia, J. R. Testa, and J. Q. Cheng ArgBP2{gamma} Interacts with Akt and p21-activated Kinase-1 and Promotes Cell Survival J. Biol. Chem., June 3, 2005; 280(22): 21483 - 21490. [Abstract] [Full Text] [PDF]

				Y. Luo, A. R. Shoemaker, X. Liu, K. W. Woods, S. A. Thomas, R. de Jong, E. K. Han, T. Li, V. S. Stoll, J. A. Powlas, et al. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo Mol. Cancer Ther., June 1, 2005; 4(6): 977 - 986. [Abstract] [Full Text] [PDF]

				L.-Y. C. Wing, H.-M. Chen, P.-C. Chuang, M.-H. Wu, and S.-J. Tsai The Mammalian Target of Rapamycin-p70 Ribosomal S6 Kinase but Not Phosphatidylinositol 3-Kinase-Akt Signaling Is Responsible for Fibroblast Growth Factor-9-induced Cell Proliferation J. Biol. Chem., May 20, 2005; 280(20): 19937 - 19947. [Abstract] [Full Text] [PDF]

				H. Takeuchi, Y. Kondo, K. Fujiwara, T. Kanzawa, H. Aoki, G. B. Mills, and S. Kondo Synergistic Augmentation of Rapamycin-Induced Autophagy in Malignant Glioma Cells by Phosphatidylinositol 3-Kinase/Protein Kinase B Inhibitors Cancer Res., April 15, 2005; 65(8): 3336 - 3346. [Abstract] [Full Text] [PDF]

				F. Lefranc, J. Brotchi, and R. Kiss Possible Future Issues in the Treatment of Glioblastomas: Special Emphasis on Cell Migration and the Resistance of Migrating Glioblastoma Cells to Apoptosis J. Clin. Oncol., April 1, 2005; 23(10): 2411 - 2422. [Abstract] [Full Text] [PDF]

				Y. Shi, A. Sharma, H. Wu, A. Lichtenstein, and J. Gera Cyclin D1 and c-myc Internal Ribosome Entry Site (IRES)-dependent Translation Is Regulated by AKT Activity and Enhanced by Rapamycin through a p38 MAPK- and ERK-dependent Pathway J. Biol. Chem., March 25, 2005; 280(12): 10964 - 10973. [Abstract] [Full Text] [PDF]

				X. Wan, A. Mendoza, C. Khanna, and L. J. Helman Rapamycin Inhibits Ezrin-Mediated Metastatic Behavior in a Murine Model of Osteosarcoma Cancer Res., March 15, 2005; 65(6): 2406 - 2411. [Abstract] [Full Text] [PDF]

				K. Inoki, H. Ouyang, Y. Li, and K.-L. Guan Signaling by Target of Rapamycin Proteins in Cell Growth Control Microbiol. Mol. Biol. Rev., March 1, 2005; 69(1): 79 - 100. [Abstract] [Full Text] [PDF]

				M. Tan, P. Li, K. S. Klos, J. Lu, K.-H. Lan, Y. Nagata, D. Fang, T. Jing, and D. Yu ErbB2 Promotes Src Synthesis and Stability: Novel Mechanisms of Src Activation That Confer Breast Cancer Metastasis Cancer Res., March 1, 2005; 65(5): 1858 - 1867. [Abstract] [Full Text] [PDF]

				L. Khamzina, A. Veilleux, S. Bergeron, and A. Marette Increased Activation of the Mammalian Target of Rapamycin Pathway in Liver and Skeletal Muscle of Obese Rats: Possible Involvement in Obesity-Linked Insulin Resistance Endocrinology, March 1, 2005; 146(3): 1473 - 1481. [Abstract] [Full Text] [PDF]

				E. V. Gerasimovskaya, D. A. Tucker, and K. R. Stenmark Activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin is necessary for hypoxia-induced pulmonary artery adventitial fibroblast proliferation J Appl Physiol, February 1, 2005; 98(2): 722 - 731. [Abstract] [Full Text] [PDF]

				E. V. Gerasimovskaya, D. A. Tucker, M. Weiser-Evans, J. M. Wenzlau, D. J. Klemm, M. Banks, and K. R. Stenmark Extracellular ATP-induced Proliferation of Adventitial Fibroblasts Requires Phosphoinositide 3-Kinase, Akt, Mammalian Target of Rapamycin, and p70 S6 Kinase Signaling Pathways J. Biol. Chem., January 21, 2005; 280(3): 1838 - 1848. [Abstract] [Full Text] [PDF]

				I. Briaud, L. M. Dickson, M. K. Lingohr, J. F. McCuaig, J. C. Lawrence, and C. J. Rhodes Insulin Receptor Substrate-2 Proteasomal Degradation Mediated by a Mammalian Target of Rapamycin (mTOR)-induced Negative Feedback Down-regulates Protein Kinase B-mediated Signaling Pathway in {beta}-Cells J. Biol. Chem., January 21, 2005; 280(3): 2282 - 2293. [Abstract] [Full Text] [PDF]

				X. Cao, F. Kambe, L. C. Moeller, S. Refetoff, and H. Seo Thyroid Hormone Induces Rapid Activation of Akt/Protein Kinase B-Mammalian Target of Rapamycin-p70S6K Cascade through Phosphatidylinositol 3-Kinase in Human Fibroblasts Mol. Endocrinol., January 1, 2005; 19(1): 102 - 112. [Abstract] [Full Text] [PDF]

				D. J. VanderWeele, R. Zhou, and C. M. Rudin Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin Mol. Cancer Ther., December 1, 2004; 3(12): 1605 - 1613. [Abstract] [Full Text] [PDF]

				M. Koziczak and N. E. Hynes Cooperation between Fibroblast Growth Factor Receptor-4 and ErbB2 in Regulation of Cyclin D1 Translation J. Biol. Chem., November 26, 2004; 279(48): 50004 - 50011. [Abstract] [Full Text] [PDF]

				J. E. Kim and J. Chen Regulation of Peroxisome Proliferator-Activated Receptor-{gamma} Activity by Mammalian Target of Rapamycin and Amino Acids in Adipogenesis Diabetes, November 1, 2004; 53(11): 2748 - 2756. [Abstract] [Full Text] [PDF]

				J. E. Thompson and C. B. Thompson Putting the Rap on Akt J. Clin. Oncol., October 15, 2004; 22(20): 4217 - 4226. [Abstract] [Full Text] [PDF]

				X. Zhou, M. Tan, V. Stone Hawthorne, K. S. Klos, K.-H. Lan, Y. Yang, W. Yang, T. L. Smith, D. Shi, and D. Yu Activation of the Akt/Mammalian Target of Rapamycin/4E-BP1 Pathway by ErbB2 Overexpression Predicts Tumor Progression in Breast Cancers Clin. Cancer Res., October 15, 2004; 10(20): 6779 - 6788. [Abstract] [Full Text] [PDF]

				W. H. Mondesire, W. Jian, H. Zhang, J. Ensor, M.-C. Hung, G. B. Mills, and F. Meric-Bernstam Targeting Mammalian Target of Rapamycin Synergistically Enhances Chemotherapy-Induced Cytotoxicity in Breast Cancer Cells Clin. Cancer Res., October 15, 2004; 10(20): 7031 - 7042. [Abstract] [Full Text] [PDF]

				J. Dong and D. Pan Tsc2 is not a critical target of Akt during normal Drosophila development Genes & Dev., October 15, 2004; 18(20): 2479 - 2484. [Abstract] [Full Text] [PDF]

				T. Yamazaki, T. Akada, O. Niizeki, T. Suzuki, H. Miyashita, and Y. Sato Puromycin-insensitive leucyl-specific aminopeptidase (PILSAP) binds and catalyzes PDK1, allowing VEGF-stimulated activation of S6K for endothelial cell proliferation and angiogenesis Blood, October 15, 2004; 104(8): 2345 - 2352. [Abstract] [Full Text] [PDF]

				I. Mothe-Satney, N. Gautier, C. Hinault, J. C. Lawrence Jr., and E. Van Obberghen In Rat Hepatocytes Glucagon Increases Mammalian Target of Rapamycin Phosphorylation on Serine 2448 but Antagonizes the Phosphorylation of Its Downstream Targets Induced by Insulin and Amino Acids J. Biol. Chem., October 8, 2004; 279(41): 42628 - 42637. [Abstract] [Full Text] [PDF]

				L. A. deGraffenried, L. Fulcher, W. E. Friedrichs, V. Grunwald, R. B. Ray, and M. Hidalgo Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway Ann. Onc., October 1, 2004; 15(10): 1510 - 1516. [Abstract] [Full Text] [PDF]

				A. D. Sinor and L. Lillien Akt-1 Expression Level Regulates CNS Precursors J. Neurosci., September 29, 2004; 24(39): 8531 - 8541. [Abstract] [Full Text] [PDF]

				M. Campbell, W. E. Allen, C. Sawyer, B. Vanhaesebroeck, and E. R. Trimble Glucose-Potentiated Chemotaxis in Human Vascular Smooth Muscle Is Dependent on Cross-Talk Between the PI3K and MAPK Signaling Pathways Circ. Res., August 20, 2004; 95(4): 380 - 388. [Abstract] [Full Text] [PDF]

				N. Hay and N. Sonenberg Upstream and downstream of mTOR Genes & Dev., August 15, 2004; 18(16): 1926 - 1945. [Abstract] [Full Text] [PDF]

				L. Hou and E. Klann Activation of the Phosphoinositide 3-Kinase-Akt-Mammalian Target of Rapamycin Signaling Pathway Is Required for Metabotropic Glutamate Receptor-Dependent Long-Term Depression J. Neurosci., July 14, 2004; 24(28): 6352 - 6361. [Abstract] [Full Text] [PDF]

				J. D. Parkington, N. K. LeBrasseur, A. P. Siebert, and R. A. Fielding Contraction-mediated mTOR, p70S6k, and ERK1/2 phosphorylation in aged skeletal muscle J Appl Physiol, July 1, 2004; 97(1): 243 - 248. [Abstract] [Full Text] [PDF]