Life's Throttle: The PI3K-PTEN-Akt-TOR Pathway in Cell Growth and Survival
Posted September 28, 2007
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Overview
We are accustomed to thinking of medical conditions as having different causes. Physicians specialize in areas such as cancer, diabetes, and diseases of aging. However, new research reveals that these seemingly disparate conditions have much in common at the biochemical level.
Cancer, diabetes, and aging are related by their use of the PI3K-PTEN-Akt-TOR signaling pathway. This pathway controls how cells grow when nutrients are available and plays a role in how caloric restriction is able to extend lifespan. If parts of the pathway malfunction due to somatic or genetic mutations, cancer or diabetes can result. Thus, the pathway presents an exciting new frontier in medicine as researchers discover how to treat diseases by stopping the propagation of harmful signals and promoting the transmission of beneficial ones.
A meeting at the Academy held on May 11, 2007, featured scientists at the forefront of the investigation into this pathway.
Web Sites
Science's Signal Transduction Knowledge Environment
Science Magazine's Signal Transduction Knowledge Environment provides perspectives, reviews, and protocols with the aim of providing access to information on cell signaling.
Journal Articles
Lewis Cantley
Engelman JA, Luo J, Cantley LC. 2006. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7: 606-619.
Isakoff SJ, Engelman JA, Irie HY, et al. 2005. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 65: 10992-11000. Full Text
Luo J, Manning BD, Cantley LC. 2003. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4: 257-262. Full Text
Luo J, McMullen JR, Sobkiw CL, et al. 2005. Class IA phosphoinositide 3-kinase regulates heart size and physiological cardiac hypertrophy. Mol. Cell Biol. 25: 9491-9502. Full Text
Luo J, Cantley LC. 2005. The negative regulation of phosphoinositide 3-kinase signaling by p85 and it's implication in cancer. Cell Cycle 4: 1309-1312. Epub 2005 Oct 28. (PDF, 237 KB) Full Text
Luo J, Sobkiw CL, Hirshman MF, et al. 2006. Loss of class IA PI3K signaling in muscle leads to impaired muscle growth, insulin response, and hyperlipidemia. Cell Metab. 3: 355-366. Full Text
Taniguchi CM, Kondo T, Sajan M, et al. 2006. Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKCλ/ζ. Cell Metab. 3: 343-353. Full Text
Ramon Parsons
Alli E, Yang J-M, Ford JM, Hait WN. 2007. Reversal of stathmin-mediated resistance to paclitaxel and vinblastine in human breast carcinoma cells. Mol. Pharmacol. 71: 1233-1240.
Bose S, Crane A, Hibshoosh H, et al. 2002. Reduced expression of PTEN correlates with breast cancer progression. Hum. Pathol. 33: 405-409.
Parsons R, Simpson L. 2003. PTEN and cancer. Methods Mol. Biol. 222: 147-166.
Podsypanina K, Lee RT, Politis C, et al. 2001. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice. Proc. Natl. Acad. Sci. USA 98: 10320-10325. Full Text
Podsypanina K, Ellenson LH, Nemes A, et al. 1999. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc. Natl. Acad. Sci. USA 96: 1563-1568. Full Text
Simpson L, Parsons R. 2001. PTEN: life as a tumor suppressor. Exp. Cell Res. 264: 29-41.
Sulis ML, Parsons R. 2003. PTEN: from pathology to biology. Trends Cell Biol. 13: 478-483.
Saal LH, Holm K, Maurer M, et al. 2005. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 65: 2554-2559. Full Text
Saal LH, Johansson P, Holm K, et al. 2007. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc. Natl. Acad. Sci. USA 104: 7564-7569. Full Text
Pier Paolo Pandolfi
Bernardi R, Guernah I, Jin D, et al. 2006. PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR. Nature 442: 779-785.
Chen Z, Trotman LC, Shaffer D, et al. 2005. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436: 725-730. FULL TEXT
Cheng K, Grisendi S, Clohessy JG, et al. 2007. The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence. Oncogene 2007 Jun 4; [Epub ahead of print]
de Stanchina E, Querido E, Narita M, et al. 2004. PML is a direct p53 target that modulates p53 effector functions. Mol. Cell. 13: 523-535. Full Text
Lin HK, Bergmann S, Pandolfi PP. 2004. Cytoplasmic PML function in TGF-β signalling. Nature 431: 205-211.
Scaglioni PP, Yung TM, Cai LF, et al. 2006. A CK2-dependent mechanism for degradation of the PML tumor suppressor. Cell 126: 269-283. Full Text
Anne Brunet
Carter ME, Brunet A. 2007. FOXO transcription factors. Curr. Biol. 17: R113-R114.
Greer EL, Brunet A. 2005. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24: 7410-74125.
Tran H, Brunet A, Griffith EC, Greenberg ME. 2003. The many forks in FOXO's road. Sci. STKE 42003: RE5.
David Sinclair
Anderson RM, Latorre-Esteves M, Neves AR, et al. 2003. Yeast life-span extension by calorie restriction is independent of NAD fluctuation. Science 302: 2124-2126.
Howitz KT, Bitterman KJ, Cohen HY, et al. 2003. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425: 191-196.
Lamming DW, Latorre-Esteves M, Medvedik O, et al. 2005. HST2 mediates SIR2-independent life-span extension by calorie restriction. Science 309: 1861-1864.
Michan S, Sinclair D. 2007. Sirtuins in mammals: insights into their biological function. Biochem. J. 404: 1-13.
Sinclair DA. 2003. Cell biology. An age of instability. Science 301: 1859-1860.
Sinclair DA. 2005. Toward a unified theory of caloric restriction and longevity regulation. Mech. Ageing Dev. 126: 987-1002.
Sinclair D, Komaroff AL. 2006. Can we slow aging? Newsweek 148: 80, 82, 84.
Sinclair DA, Lin SJ, Guarente L. 2006. Life-span extension in yeast. Science 312: 195-197.
Wood JG, Rogina B, Lavu S, et al. 2004. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430: 686-689.
Domenico Accili
Adachi M, Osawa Y, Uchinami H, et al. 2007. The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells. Gastroenterology 132:1434-1446. Epub 2007 Jan 25.
Buteau J, Spatz ML, Accili D. 2006. Transcription factor FoxO1 mediates glucagon-like peptide-1 effects on pancreatic β-cell mass. Diabetes 55: 1190-1196. Full Text
Buteau J, Shlien A, Foisy S, Accili D. 2007. Metabolic diapause in pancreatic β-cells expressing a gain-of-function mutant of the forkhead protein Foxo1. J. Biol. Chem. 282: 287-293.
Frescas D, Valenti L, Accili D. 2005. Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J. Biol. Chem. 280: 20589-20595. Full Text
Kim JJ, Kido Y, Scherer PE, et al. 2007. Analysis of compensatory β-cell response in mice with combined mutations of Insr and Irs2. Am. J. Physiol. Endocrinol. Metab. 292: E1694-1701. [PubMed - in process]
Kitamura YI, Kitamura T, Kruse JP, et al. 2005. FoxO1 protects against pancreatic β cell failure through NeuroD and MafA induction. Cell Metab. 2: 153-163. Full Text
Kitamura T, Feng Y, Kitamura YI, et al. 2006. Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Nat. Med. 12: 534-540.
Matsumoto M, Accili D. 2005. All roads lead to FoxO. Cell Metab. 1: 215-216. Full Text
Matsumoto M, Han S, Kitamura T, Accili D. 2006. Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J. Clin. Invest. 116: 2464-2472. Full Text
Naimi M, Gautier N, Chaussade C, et al. 2007. Nuclear forkhead box O1 controls and integrates key signaling pathways in hepatocytes. Endocrinology 148: 2424-2434.
Okamoto H, Hribal ML, Lin HV, et al. 2006. Role of the forkhead protein FoxO1 in β cell compensation to insulin resistance. J. Clin. Invest. 116: 775-782. Full Text
George Thomas
Cota D, Proulx K, Smith KA, et al. 2006. Hypothalamic mTOR signaling regulates food intake. Science 312: 927-930.
Dann SG, Thomas G. 2006. The amino acid sensitive TOR pathway from yeast to mammals. FEBS Lett. 580: 2821-2829.Dann SG, Selvaraj A, Thomas G. 2007. mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol. Med. 13: 252-259.
Gulati P, Thomas G. 2007. Nutrient sensing in the mTOR/S6K1 signalling pathway. Biochem. Soc. Trans. 35 (Pt 2): 236-238.
Nobukuni T, Kozma SC, Thomas G. 2007. hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling. Curr. Opin. Cell Biol. 19: 135-141.
Um SH, D'Alessio D, Thomas G. 2006. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab. 3: 393-402. Full Text
Barbara Kahn
Bence KK, Delibegovic M, Xue B, et al. 2006. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat. Med. 12: 917-924.
Galic S, Hauser C, Kahn BB, et al. 2005. Coordinated regulation of insulin signaling by the protein tyrosine phosphatases PTP1B and TCPTP. Mol. Cell Biol. 25: 819-829. Full Text
Haj FG, Zabolotny JM, Kim YB, et al. 2005. Liver-specific protein-tyrosine phosphatase 1B (PTP1B) re-expression alters glucose homeostasis of PTP1B−/−mice. J. Biol. Chem. 280: 15038-15046. Full Text
Kahn BB, Alquier T, Carling D, Hardie DG. 2005. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 1: 15-25. Full Text
Martin TL, Alquier T, Asakura K, et al. 2006. Diet-induced obesity alters AMP-kinase activity in hypothalamus and skeletal muscle. J. Biol. Chem. 281: 18933-18941. Full Text
Minokoshi Y, Kim Y-B, Peroni OD, et al. 2002. Leptin stimulates fatty acid oxidation by activation of AMP-activated protein kinase. Nature 415: 339-343.
Minokoshi Y, Alquier T, Furukawa N, et al. 2004. AMP-activated protein kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428: 569-574.
Venable CL, Frevert EU, Kim YB. 2000. Overexpression of protein-tyrosine phosphatase-1B in adipocytes inhibits insulin-stimulated phosphoinositide 3-kinase activity without altering glucose transport or Akt/Protein kinase B activation. J. Biol. Chem. 275: 18318-18326. Full Text
Xue B, Kim YB, Lee A, et al. 2007. Protein tyrosine phosphatase 1B (PTB1B) deficiency reduces insulin resistance and the diabetic phenotype in mice with polygenic insulin resistance. J. Biol. Chem. 2007 Jun 1; [Epub ahead of print]
Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, et al. 2002. PTP1B regulates leptin signal transduction in vivo. Dev. Cell. 2: 489-495. Full Text
Zabolotny JM, Haj FG, Kim YB, et al. 2004. Transgenic overexpression of protein-tyrosine phosphatase 1B in muscle causes insulin resistance, but overexpression with leukocyte antigen-related phosphatase does not additively impair insulin action. J. Biol. Chem. 279: 24844-24851. Full Text
Peter Finan
Thomas MJ, Smith A, Head DH, et al. 2005. Airway inflammation: chemokine-induced neutrophilia and the class I phosphoinositide 3-kinases. Eur. J. Immunol. 35: 1283-1291.
Ward SG, Finan P. 2003. Isoform-specific phosphoinositide 3-kinase inhibitors as therapeutic agents. Curr. Opin. Pharmacol. 3: 426-434.
Ward S, Sotsios Y, Dowden J, et al. 2003. Therapeutic potential of phosphoinositide 3-kinase inhibitors. Chem. Biol. 10: 207-213. Full Text
Ward SG, Finan P, Welham MJ. 2003. PI3K comes of age. Nat. Immunol. 4: 2.
Wymann MP, Björklöf K, Calvez R, Finan P. 2003. Phosphoinositide 3-kinase γ: a key modulator in inflammation and allergy. Biochem. Soc. Trans. 31 (Pt 1): 275-280. Full Text
David Sabatini
Ali SM, Sabatini DM. 2005. Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site. J. Biol. Chem. 280: 19445-19448. Full Text
Frias MA, Thoreen CC, Jaffe JD, et al. 2006. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr. Biol. 16: 1865-1870.
Guertin DA, Sabatini DM. 2005. An expanding role for mTOR in cancer. Trends Mol. Med. 11: 353-361.
Guertin DA, Stevens DM, Thoreen CC, et al. 2006. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev. Cell 11: 859-871.
Reiling JH, Sabatini DM. 2006. Stress and mTORture signaling. Oncogene 25: 6373-6383.
Sabatini DM. 2006. mTOR and cancer: insights into a complex relationship. Nat. Rev. Cancer 6: 729-734.
Sarbassov DD, Ali SM, Sabatini DM. 2005. Growing roles for the mTOR pathway. Curr. Opin. Cell Biol. 17: 596-603.
Sarbassov DD, Sabatini DM. 2005. Redox regulation of the nutrient-sensitive raptor-mTOR pathway and complex. J. Biol. Chem. 280: 39505-39509. Full Text
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. 2005. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307: 1098-1101.
Sarbassov DD, Ali SM, Sengupta S, et al. 2006. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22: 159-168. Full Text
Zeng Z, Sarbassov DD, Samudio IJ, et al. 2007. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109: 3509-3512.
Charles Sawyers
Mehrian-Shai R, Chen CD, Shi T, et al. 2007. Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. Proc. Natl. Acad. Sci. USA 104: 5563-5568.
Mellinghoff IK, Sawyers CL. 2004. TORward AKTually useful mouse models. Nat. Med. 10: 579-580.
Vivanco I, Palaskas N, Tran C, et al. 2007. Identification of the JNK signaling pathway as a functional target of the tumor suppressor PTEN. Cancer Cell 11: 555-569.
Wang MY, Lu KV, Zhu S, et al. 2006. Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res. 66: 7864-7869. Full Text
Speakers
Lewis C. Cantley, PhD
Harvard Medical School and Beth Israel Deaconess Medical Center
e-mail | web site | publications
Lewis C. Cantley joined the faculty of Harvard Medical School in 1992, when he was also appointed chief of the Division of Signal Transduction in the Department of Medicine at Beth Israel Hospital. He earned his PhD from Cornell University in 1975. His postdoctoral research and first faculty appointment were in the Department of Biochemistry and Molecular Biology at Harvard University. Prior to joining Harvard Medical School, Cantley was professor of physiology at Tufts University School of Medicine.
Ramon Parsons, MD, PhD
Columbia University
e-mail | web site | publications
Ramon Parsons is the Avon Foundation Associate Professor of Breast Cancer Research in the Institute for Cancer Genetics and in the Herbert Irving Comprehensive Cancer Center at Columbia University.
Pier Paolo Pandolfi, MD, PhD
Beth Israel Deaconess Medical Center
e-mail | publications
Pier Paolo Pandolfi recently joined the faculty of Beth Israel Deaconess Medical Center (BIDMC) where he holds joint appointments in the Department of Pathology and the Department of Medicine. He is also the director of the new Cancer Genetics Center at BIDMC as well as a professor of medicine and pathology at Harvard Medical School.
Pandolfi moved to BIDMC from New York's Memorial Sloan-Kettering Cancer Center, where he held the Albert C. Foster Chair in Cancer Biology and Genetics and was professor of molecular biology and genetics at Weill Graduate School of Medical Sciences as well as professor of pathology at Weill Medical College of Cornell University. Pandolfi received his MD in 1989 and his PhD in 1995 from the University of Perugia, Italy.
Anne Brunet, PhD
Stanford University School of Medicine
e-mail | web site | publications
Anne Brunet is an assistant professor in the Department of Genetics at Stanford University School of Medicine. Brunet received her PhD in biology in 1997 from Université de Nice, France and completed postdoctoral training in Michael E. Greenberg's lab at Harvard Medical School. Her honors include an award from the Human Frontier Science Program and the Goldenson-Berenberg Fellowship for postdoctoral training. In 2003, she received the Prix L. LaCaze et A. Policart-Lacassagne for junior scientists from the French National Academy of Sciences.
David A. Sinclair, PhD
Harvard Medical School
e-mail | web site | publications
David Sinclair is an associate professor of pathology and director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School. Sinclair holds a PhD in biochemistry and molecular genetics from the University of New South Wales, Australia. He worked as a postdoctoral researcher at M.I.T. with Leonard Guarente before being recruited in 1999 to Harvard Medical School.
Domenico Accili, MD
Columbia University
e-mail | web site | publications
Domenico Accili is professor of medicine at Columbia University, attending physician at Columbia-Presbyterian Hospital, and director of the Columbia University Diabetes and Endocrinology Research Center in New York, NY. A graduate of the University of Rome School of Medicine in Italy, he trained in medicine at the University Hospital, Agostino Gemelli, also in Rome. Following a Fogarty Fellowship in the Diabetes Branch of the National Institute of Diabetes and Digestive and Kidney diseases, he became chief of the Section on Genetics and Hormone action of the National Institute of Child Health at the National Institutes of Health in Bethesda, Maryland. Since 1999, he has served on the faculty at Columbia University.
George Thomas, PhD
University of Cincinnati
e-mail | web site | publications
George Thomas is interim chairman of the department of genome science and interim director of the Genome Research Institute at the University of Cincinnati. He received his PhD from UC Santa Cruz in 1975. He then moved to the Friedrich Miescher Institute for Biomedical Research (FMI) in Basel, Switzerland in 1975 as a fellow of the European Molecular Biology Organization. In 1979 he became a junior group leader at the FMI and in 1983 he was promoted to senior group leader. In 1991 he became a member of EMBO and in 1995 was awarded the Max Cloëtta Prize for Medical Research.
Barbara B. Kahn, MD
Beth Israel Deaconess Medical Center
e-mail | web site | publications
Barbara Kahn is professor of medicine, chief of the Endocrinology, Diabetes, and Metabolism Division at Beth Israel Deaconess Medical Center, chief of the joint Endocrinology Program, and associate director of the NIH-funded Boston Obesity Nutrition Research Center. Kahn has an MS from the University of California Berkeley, Health and Medical Sciences and an MD from Stanford University Medical School.
Peter Finan, PhD
Novartis Institutes for Biomedical Research
e-mail | web site | publications
Peter Finan is the phosphoinositide 3-kinase (PI3-kinase) project team head in Respiratory Diseases based at Novartis Horsham Research Centre, Uk.
David Sabatini, MD, PhD
Whitehead Institute for Biomedical Research
e-mail | web site | publications
David Sabatini is a member of the Whitehead Institute for Biomedical Research, an associate member of the Broad Institute and the MIT Center for Cancer Research, and an associate professor in the Department of Biology at Massachusetts Institute of Technology. Sabatini holds an MD and PhD from Johns Hopkins University School of Medicine.
Charles L. Sawyers, MD
Memorial Sloan-Kettering Cancer Center
e-mail | web site | publications
Charles Sawyers is chairman of Memorial Sloan-Kettering Cancer Center's Human Oncology and Pathogenesis Program (HOPP) and the first incumbent of the Marie José and Henry R. Kravis Chair. He received his medical degree from The Johns Hopkins University. He completed a residency in internal medicine at the University of California, San Francisco, Medical Center and a clinical fellowship in hematology/oncology at the UCLA School of Medicine. He is also a Howard Hughes Medical Institute Investigator.
Catherine Zandonella
Catherine Zandonella is a science writer based in New York City, covering such topics as environmental science, public health, and applied technology. She has a master's degree in public health from the University of California, Berkeley. Zandonella has written for a number of publications, including New Scientist, The Scientist, and Nature.