1 phosphatidylinositol 3 kinase

Summary

Summary: An enzyme that catalyzes the conversion of phosphatidylinositol to phosphatidylinositol 3-phosphate. This is the first committed step in the biosynthesis of phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. This pathway is thought to play a critical role in DNA repair, V(D)J recombination and cell cycle checkpoints. EC 2.7.1.137.

Top Publications

  1. ncbi The phosphatidylinositol 3-Kinase AKT pathway in human cancer
    Igor Vivanco
    Department of Medicine and Molecular Biology Institute, UCLA School of Medicine, 11 935 Factor Building, 10833 LeConte Avenue, Los Angeles, California 90095, USA
    Nat Rev Cancer 2:489-501. 2002
  2. ncbi The phosphoinositide 3-kinase pathway
    Lewis C Cantley
    Department of Cell Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115 5713, USA
    Science 296:1655-7. 2002
  3. ncbi Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
    D D Sarbassov
    Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA
    Science 307:1098-101. 2005
  4. ncbi The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate
    T Maehama
    Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109 0606, USA
    J Biol Chem 273:13375-8. 1998
  5. ncbi High frequency of mutations of the PIK3CA gene in human cancers
    Yardena Samuels
    Sidney Kimmel Comprehensive Cancer Center, Howard Hughes Medical Institute, The Johns Hopkins University Medical Institutions, Baltimore, MD 21231, USA
    Science 304:554. 2004
  6. ncbi The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
    Jeffrey A Engelman
    Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Rev Genet 7:606-19. 2006
  7. ncbi Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control
    Robbie Loewith
    Division of Biochemistry, Biozentrum, University of Basel, Klingelbergstrasse 70, CH 4056 Basel, Switzerland
    Mol Cell 10:457-68. 2002
  8. ncbi Cellular survival: a play in three Akts
    S R Datta
    Division of Neuroscience, Children s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115 USA
    Genes Dev 13:2905-27. 1999
  9. pmc mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt
    Kathryn E O'Reilly
    Program in Molecular Pharmacy and Chemistry, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    Cancer Res 66:1500-8. 2006
  10. ncbi Critical nodes in signalling pathways: insights into insulin action
    Cullen M Taniguchi
    Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215, USA
    Nat Rev Mol Cell Biol 7:85-96. 2006

Detail Information

Publications279 found, 100 shown here

  1. ncbi The phosphatidylinositol 3-Kinase AKT pathway in human cancer
    Igor Vivanco
    Department of Medicine and Molecular Biology Institute, UCLA School of Medicine, 11 935 Factor Building, 10833 LeConte Avenue, Los Angeles, California 90095, USA
    Nat Rev Cancer 2:489-501. 2002
  2. ncbi The phosphoinositide 3-kinase pathway
    Lewis C Cantley
    Department of Cell Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115 5713, USA
    Science 296:1655-7. 2002
    ..The PI3K pathway is implicated in human diseases including diabetes and cancer, and understanding the intricacies of this pathway may provide new avenues for therapuetic intervention...
  3. ncbi Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
    D D Sarbassov
    Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA
    Science 307:1098-101. 2005
    ..Rictor-mTOR may serve as a drug target in tumors that have lost the expression of PTEN, a tumor suppressor that opposes Akt/PKB activation...
  4. ncbi The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate
    T Maehama
    Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109 0606, USA
    J Biol Chem 273:13375-8. 1998
    ..As expected, the C124S mutant of PTEN was incapable of catalyzing dephosphorylation of PtdIns(3,4,5)P3 consistent with the mechanism observed in protein-tyrosine phosphatase-catalyzed reactions...
  5. ncbi High frequency of mutations of the PIK3CA gene in human cancers
    Yardena Samuels
    Sidney Kimmel Comprehensive Cancer Center, Howard Hughes Medical Institute, The Johns Hopkins University Medical Institutions, Baltimore, MD 21231, USA
    Science 304:554. 2004
  6. ncbi The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
    Jeffrey A Engelman
    Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nat Rev Genet 7:606-19. 2006
    ..In light of the recent advances in our understanding of the function of PI3Ks in the pathogenesis of diabetes and cancer, we discuss the exciting therapeutic opportunities for targeting this pathway to treat these diseases...
  7. ncbi Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control
    Robbie Loewith
    Division of Biochemistry, Biozentrum, University of Basel, Klingelbergstrasse 70, CH 4056 Basel, Switzerland
    Mol Cell 10:457-68. 2002
    ..Thus, the distinct TOR complexes account for the diversity, specificity, and selective rapamycin inhibition of TOR signaling. TORC1 and possibly TORC2 are conserved from yeast to man...
  8. ncbi Cellular survival: a play in three Akts
    S R Datta
    Division of Neuroscience, Children s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115 USA
    Genes Dev 13:2905-27. 1999
  9. pmc mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt
    Kathryn E O'Reilly
    Program in Molecular Pharmacy and Chemistry, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
    Cancer Res 66:1500-8. 2006
    ..Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity...
  10. ncbi Critical nodes in signalling pathways: insights into insulin action
    Cullen M Taniguchi
    Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215, USA
    Nat Rev Mol Cell Biol 7:85-96. 2006
    ..Here, we use the concept of 'critical nodes' to define the important junctions in these pathways and illustrate their unique role using insulin signalling as a model system...
  11. ncbi Ras, PI(3)K and mTOR signalling controls tumour cell growth
    Reuben J Shaw
    Dulbecco Laboratory for Cancer Research, The Salk Institute, 10010 N Torrey Pines Road, La Jolla, California 9203, USA
    Nature 441:424-30. 2006
    ..The preponderance of mutations in these interconnected pathways suggests that the loss of growth-control checkpoints and promotion of cell survival in nutrient-limited conditions may be an obligate event in tumorigenesis...
  12. ncbi 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
    Sauveur Michel Maira
    Oncology Disease Area, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH4002 Basel, Switzerland
    Mol Cancer Ther 7:1851-63. 2008
    ..Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials...
  13. ncbi Exploiting the PI3K/AKT pathway for cancer drug discovery
    Bryan T Hennessy
    Department of Molecular Therapeutics, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
    Nat Rev Drug Discov 4:988-1004. 2005
    ..This warrants exploiting the PI3K/AKT pathway for cancer drug discovery...
  14. ncbi Defining the role of mTOR in cancer
    David A Guertin
    Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Cambridge, MA 02141, USA
    Cancer Cell 12:9-22. 2007
    ..We further discuss the use of rapamycin in oncology and conclude with a discussion on the future of mTOR-targeted therapy...
  15. ncbi NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase
    O N Ozes
    Department of Microbiology and Immunology, Indiana University School of Medicine, The Walther Oncology Center, Indianapolis 46202, USA
    Nature 401:82-5. 1999
    ..Mutation of this amino acid blocks phosphorylation by Akt or TNF and activation of NF-kappaB. These findings indicate that Akt is part of a signalling pathway that is necessary for inducing key immune and inflammatory responses...
  16. ncbi Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis
    Megan Cully
    The Campbell Family Institute for Breast Cancer Research, University Health Network, University of Toronto, Toronto, Ontario M5G 2C1, Canada
    Nat Rev Cancer 6:184-92. 2006
    ..How does the PI3K pathway integrate signals from numerous sources, and how can this information be used in the rational design of cancer therapies?..
  17. ncbi Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway
    Brendan D Manning
    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Mol Cell 10:151-62. 2002
    ..Finally, we find that a tuberin mutant lacking the major PI3K-dependent phosphorylation sites can block the activation of S6K1, suggesting a means by which the PI3K-Akt pathway regulates S6K1 activity...
  18. ncbi Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt
    L del Peso
    Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    Science 278:687-9. 1997
    ..Thus, the proapoptotic function of BAD is regulated by the PI 3-kinase-Akt pathway...
  19. ncbi RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs
    D M Sabatini
    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
    Cell 78:35-43. 1994
    ..We propose that RAFT1 is the direct target of FKBP12-rapamycin and a mammalian homolog of the TOR proteins...
  20. ncbi Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice
    H Cho
    Department of Biology, University of Pennsylvania, Philadelphia 19104, USA
    J Biol Chem 276:38349-52. 2001
    ....
  21. ncbi Xid-like immunodeficiency in mice with disruption of the p85alpha subunit of phosphoinositide 3-kinase
    H Suzuki
    Department of Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku ku, Tokyo 160 8582, Japan
    Science 283:390-2. 1999
    ..These results provide evidence that p85alpha is functionally linked to the Btk pathway in antigen receptor-mediated signal transduction and is pivotal in B cell development and functions...
  22. ncbi Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation
    J Brognard
    Developmental Therapeutics Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20889, USA
    Cancer Res 61:3986-97. 2001
    ....
  23. ncbi Regulation of translation initiation by FRAP/mTOR
    A C Gingras
    Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada
    Genes Dev 15:807-26. 2001
  24. ncbi Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation
    E Hirsch
    Department of Genetics, Biology and Biochemistry, University of Torino, Turin, Italy
    Science 287:1049-53. 2000
    ..These results demonstrate that PI3Kgamma is a crucial signaling molecule required for macrophage accumulation in inflammation...
  25. ncbi The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells
    Mausumee Guha
    Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 277:32124-32. 2002
    ..Our study provides new insight into the inhibitory mechanism by which the PI3K-Akt pathway ensures transient expression of these potent inflammatory mediators...
  26. ncbi Mutation of the PIK3CA gene in ovarian and breast cancer
    Ian G Campbell
    VBCRC Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
    Cancer Res 64:7678-81. 2004
    ..5% of all ovarian cancers and 45% of the endometrioid and clear cell subtypes. Our study is the first direct evidence that PIK3CA is an oncogene in ovarian cancer and greatly extends recent findings in breast cancer...
  27. ncbi EEA1 links PI(3)K function to Rab5 regulation of endosome fusion
    A Simonsen
    Department of Biochemistry, The Norwegian Radium Hospital, Montebello, Oslo
    Nature 394:494-8. 1998
    ....
  28. ncbi The PIK3CA gene is mutated with high frequency in human breast cancers
    Kurtis E Bachman
    The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Department of Oncology, Baltimore, Maryland 21231, USA
    Cancer Biol Ther 3:772-5. 2004
    ..These results demonstrate that PIK3CA is the most mutated oncogene in breast cancer and support a role for PIK3CA in epithelial carcinogenesis...
  29. ncbi Oncogenic PI3K deregulates transcription and translation
    Andreas G Bader
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    Nat Rev Cancer 5:921-9. 2005
    ....
  30. ncbi The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase
    T F Franke
    Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
    Cell 81:727-36. 1995
    ..These results identify Akt as a novel target of PI 3-kinase and suggest that the Akt PH domain may be a mediator of PI 3-kinase signaling...
  31. ncbi Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer
    R Katso
    Ludwig Institute for Cancer Research, 91 Riding House Street, London, W1W 7BS, England
    Annu Rev Cell Dev Biol 17:615-75. 2001
    ..The evidence for the role of deregulated PI3K signaling in diseases such as cancer and diabetes is reviewed...
  32. ncbi Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway
    A Brunet
    Division of Neuroscience, Children s Hospital and Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
    Curr Opin Neurobiol 11:297-305. 2001
    ..In addition, recent experiments suggest that Akt may also use metabolic pathways to regulate cell survival...
  33. pmc Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic
    Sohye Kang
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 102:802-7. 2005
    ..The oncogenic transforming activity makes the mutated PI3-kinase proteins promising targets for small molecule inhibitors that could be developed into effective and highly specific anticancer drugs...
  34. pmc Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase
    Takahiro Nobukuni
    Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland
    Proc Natl Acad Sci U S A 102:14238-43. 2005
    ....
  35. pmc Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1
    A H Kim
    Molecular Neurobiology Program, Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA
    Mol Cell Biol 21:893-901. 2001
    ..These results provide the first direct link between Akt and the family of stress-activated kinases...
  36. ncbi A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans
    J Z Morris
    Department of Molecular Biology, Massachusetts General Hospital, Boston 02114, USA
    Nature 382:536-9. 1996
    ..These data suggest that phosphatidylinositol signalling mediated by AGE-1 protein controls lifespan and the dauer diapause decision...
  37. ncbi Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration
    T Sasaki
    Amgen Institute, 620 University Avenue, Toronto M5G 2C1, Ontario, Canada
    Science 287:1040-6. 2000
    ..Thus, PI3Kgamma regulates thymocyte development, T cell activation, neutrophil migration, and the oxidative burst...
  38. ncbi Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines
    Antoinette Hollestelle
    Department of Medical Oncology, Josephine Nefkens Institute Be414, Erasmus MC, P O Box 1738, 3000 DR Rotterdam, The Netherlands
    Mol Cancer Res 5:195-201. 2007
    ..001). These results suggest that there is a fine distinction between the signaling activators and downstream effectors of the oncogenic PI3K and RAS pathways in breast epithelium and those in other tissues...
  39. ncbi A mammalian protein targeted by G1-arresting rapamycin-receptor complex
    E J Brown
    Department of Chemistry, Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138
    Nature 369:756-8. 1994
    ....
  40. ncbi Phosphatidic acid-mediated mitogenic activation of mTOR signaling
    Y Fang
    Department of Cell and Structural Biology, University of Illinois at Urbana Champaign, 601 South Goodwin Avenue, B107, Urbana, IL 61801, USA
    Science 294:1942-5. 2001
    ..Furthermore, these studies suggest a potential mechanism for the in vivo actions of the immunosuppressant rapamycin...
  41. ncbi Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy
    F Chang
    Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville 27858, USA
    Leukemia 17:590-603. 2003
    ..Furthermore, strategies used to inhibit the PI3K/Akt pathway are presented. The potential for cancer treatment with agents inhibiting this pathway is also addressed...
  42. ncbi Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice
    Klaus Okkenhaug
    Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK
    Science 297:1031-4. 2002
    ..They also developed inflammatory bowel disease. These results reveal a selective role for p110delta in immunity...
  43. ncbi A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer
    Katrien Berns
    Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
    Cancer Cell 12:395-402. 2007
    ..Thus, assessment of PI3K pathway activation may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy...
  44. ncbi PKB/AKT: functional insights from genetic models
    M P Scheid
    Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9
    Nat Rev Mol Cell Biol 2:760-8. 2001
    ....
  45. ncbi A nutrient sensor mechanism controls Drosophila growth
    Julien Colombani
    Institute for Signaling, Developmental Biology and Cancer Research, UMR6543 CNRS Parc Valrose, 06108, Cedex 2, Nice, France
    Cell 114:739-49. 2003
    ..Our results demonstrate that the fat body functions as a nutrient sensor that restricts global growth through a humoral mechanism...
  46. pmc An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer
    Katherine Stemke-Hale
    Department of Systems Biology, The University of Texas MD Anderson Cancer, Houston, Texas 77030, USA
    Cancer Res 68:6084-91. 2008
    ..The specific aberration present may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer...
  47. ncbi Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1
    J A Le Good
    Protein Phosphorylation Laboratory, Imperial Cancer Research Fund, 44 Lincoln s Inn Fields, London WC2A 3PX, UK
    Science 281:2042-5. 1998
    ..The activation loop phosphorylation of PKCdelta in response to serum stimulation of cells was PI 3-kinase-dependent and was enhanced by PDK1 coexpression...
  48. pmc Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms
    Li Zhao
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037
    Proc Natl Acad Sci U S A 105:2652-7. 2008
    ..This synergism also supports the conclusion that the helical and kinase domain mutations operate by two different and independent mechanisms...
  49. ncbi Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit
    Nabil Miled
    Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK
    Science 317:239-42. 2007
    ..These studies extend our understanding of the architecture of PI3Ks and provide insight into how two classes of mutations that cause a gain in function can lead to cancer...
  50. ncbi Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance
    R A Campbell
    Department of Surgery, Indiana University School of Medicine, Indianapolis 46202, USA
    J Biol Chem 276:9817-24. 2001
    ..Taken together, these results define a molecular link between activation of the PI 3-kinase/AKT survival pathways, hormone-independent activation of ERalpha, and inhibition of tamoxifen-induced apoptotic regression...
  51. pmc PI3K pathway alterations in cancer: variations on a theme
    T L Yuan
    Department of Systems Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 2115, USA
    Oncogene 27:5497-510. 2008
    ..In this review, we will examine the oncogenic properties of these genetic alterations to understand whether they are redundant or distinct and propose treatment strategies tailored for these genetic lesions...
  52. pmc Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest
    R A Fratti
    Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    J Cell Biol 154:631-44. 2001
    ..tuberculosis. This study also identifies mycobacterial phosphoinositides as products with specialized toxic properties, interfering with discrete trafficking stages in phagosomal maturation...
  53. ncbi Colorectal cancer: mutations in a signalling pathway
    D Williams Parsons
    The Sidney Kimmel Comprehensive Cancer Center and The Howard Hughes Medical Institute, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21231, USA
    Nature 436:792. 2005
    ..The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for therapeutic intervention...
  54. ncbi PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients
    Yoichi Nagata
    Department of Surgical Oncology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Cancer Cell 6:117-27. 2004
    ..Thus, PTEN deficiency is a powerful predictor for trastuzumab resistance. Additionally, PI3K inhibitors rescued PTEN loss-induced trastuzumab resistance, suggesting that PI3K-targeting therapies could overcome this resistance...
  55. pmc Cdc42, Rac1, and Rac2 display distinct patterns of activation during phagocytosis
    Adam D Hoppe
    Department of Microbiology and Immunology and the Biophysics Research Division, University of Michigan Medical School, Ann Arbor, Michigan 48109 0620, USA
    Mol Biol Cell 15:3509-19. 2004
    ..These distinct roles for Cdc42, Rac1, and Rac2 in the component activities of phagocytosis indicate mechanisms by which their differential regulation coordinates rearrangements of actin and membranes...
  56. pmc Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase
    T Simoncini
    Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 407:538-41. 2000
    ..Our findings define a physiologically important non-nuclear oestrogen-signalling pathway involving the direct interaction of ER alpha with PI(3)K...
  57. ncbi PI3K and negative regulation of TLR signaling
    Taro Fukao
    Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku ku, 160 8582, Tokyo, Japan
    Trends Immunol 24:358-63. 2003
    ..Thus, PI3K, IRAK-M and SOCS-1 have unique roles in the gate-keeping system, preventing excessive innate immune responses...
  58. pmc Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis
    Yoshinori Takahashi
    H Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive Tampa, FL 33612, USA
    Nat Cell Biol 9:1142-51. 2007
    ..Moreover, knockout of Bif-1 significantly enhances the development of spontaneous tumours in mice. These findings suggest that Bif-1 joins the UVRAG-Beclin 1 complex as a potential activator of autophagy and tumour suppressor...
  59. ncbi The PTEN-PI3K pathway: of feedbacks and cross-talks
    A Carracedo
    Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Harvard Medical School, Boston, MA 02215, USA
    Oncogene 27:5527-41. 2008
    ..This provides novel provocative therapeutic implications based on the targeted modulation of PI3K-cross-talking signals...
  60. pmc Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase
    M Delcommenne
    British Columbia Cancer Agency, Jack Bell Research Centre, 2660 Oak Street, Vancouver, British Columbia V6H 3Z6 Canada
    Proc Natl Acad Sci U S A 95:11211-6. 1998
    ..ILK is thus a receptor-proximal effector for the Pi(3)K-dependent, extracellular matrix and growth factor mediated, activation of PKB/AKT, and inhibition of GSK-3...
  61. pmc Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis
    Shidong Jia
    Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
    Nature 454:776-9. 2008
    ..Taken together, our findings demonstrate both kinase-dependent and kinase-independent functions for p110beta, and strongly indicate the kinase-dependent functions of p110beta as a promising target in cancer therapy...
  62. ncbi Chemotaxis in the absence of PIP3 gradients
    Oliver Hoeller
    Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK
    Curr Biol 17:813-7. 2007
    ..A signaling pathway from receptor to cytoskeleton able to guide cells independently of polarized PIP3 and type-1 phosphoinositide 3-kinases must exist...
  63. ncbi HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells
    Christiane Knuefermann
    Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
    Oncogene 22:3205-12. 2003
    ....
  64. pmc Hrs, a FYVE finger protein localized to early endosomes, is implicated in vesicular traffic and required for ventral folding morphogenesis
    M Komada
    Program in Developmental Biology, Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
    Genes Dev 13:1475-85. 1999
    ..The vesicular localization of Hrs was disrupted in cells treated with wortmannin, implicating Hrs in the phosphatidylinositol 3-kinase pathway of membrane trafficking...
  65. ncbi Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene
    E Araki
    Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
    Nature 372:186-90. 1994
    ..Our results provide evidence for IRS-1-dependent and IRS-1-independent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases...
  66. pmc The PI3K-PDK1 connection: more than just a road to PKB
    B Vanhaesebroeck
    Cell Signalling Group, Ludwig Institute for Cancer Research, 91 Riding House Street, London W1P 8BT, U K
    Biochem J 346:561-76. 2000
    ....
  67. ncbi Oncogenic mutations of PIK3CA in human cancers
    Yardena Samuels
    The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21231, USA
    Cell Cycle 3:1221-4. 2004
    ..PIK3CA represents one of the most highly mutated oncogenes identified in human cancers and may be a useful diagnostic and therapeutic target...
  68. ncbi Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway
    L Arbibe
    Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA
    Nat Immunol 1:533-40. 2000
    ..Thus Rac1 controls a second, I kappa B-independent, pathway to NF-kappa B activation and is essential in innate immune cell signaling via TLR2...
  69. ncbi Control of dendritic arborization by the phosphoinositide-3'-kinase-Akt-mammalian target of rapamycin pathway
    Jacek Jaworski
    The Picower Institute for Learning and Memory, The Institute of Physical and Chemical Research RIKEN, Massachusetts Institute of Technology Neuroscience Research Center, Cambridge, Massachusetts 02139, USA
    J Neurosci 25:11300-12. 2005
    ....
  70. ncbi Phosphatidylinositol-3-OH Kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K
    M Sun
    Department of Pathology and Programs of Molecular Oncology and Drug Discovery, University of South Florida College of Medicine and H Lee Moffitt Cancer Center, Tampa, Florida 33612, USA
    Cancer Res 61:5985-91. 2001
    ....
  71. ncbi Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation
    Lazaros C Foukas
    Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK
    Nature 441:366-70. 2006
    ..These findings demonstrate a critical role for p110alpha in growth factor and metabolic signalling and also suggest an explanation for selective mutation or overexpression of p110alpha in a variety of cancers...
  72. ncbi ATM and related protein kinases: safeguarding genome integrity
    Yosef Shiloh
    The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
    Nat Rev Cancer 3:155-68. 2003
    ..Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers...
  73. ncbi Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways
    Lionel Larue
    Developmental Genetics of Melanocytes, UMR 146, CNRS, Institut Curie, Centre Universitaire, Orsay, France
    Oncogene 24:7443-54. 2005
    ..Interactions between PI3K/AKT and other EMT-inducing pathways are presented, along with a discussion of the therapeutic implications of modulating EMT in order to achieve cancer control...
  74. ncbi Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death
    Alexander Arlt
    1Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Medicine, University of Kiel, Germany
    Oncogene 22:3243-51. 2003
    ....
  75. pmc New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway
    L C Cantley
    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 96:4240-5. 1999
    ..PTEN appears to negatively control the phosphoinositide 3-kinase signaling pathway for regulation of cell growth and survival by dephosphorylating the 3 position of phosphoinositides...
  76. pmc A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling
    Zachary A Knight
    Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA
    Cell 125:733-47. 2006
    ..These results illustrate systematic target validation using a matrix of inhibitors that span a protein family...
  77. ncbi Signalling through the lipid products of phosphoinositide-3-OH kinase
    A Toker
    Boston Biomedical Research Institute, Massachusetts 02114, USA
    Nature 387:673-6. 1997
    ..But how PI(3)K mediates these responses is only now becoming clear...
  78. pmc Redox regulation of PI 3-kinase signalling via inactivation of PTEN
    Nick R Leslie
    Division of Cell Signalling, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
    EMBO J 22:5501-10. 2003
    ..These results may have significant implications for the many cellular processes in which PtdIns(3,4,5)P(3) and oxidants are produced concurrently...
  79. ncbi Phosphoinositide 3-kinase signalling pathways
    D A Cantrell
    Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London, WC2A 3PX, UK
    J Cell Sci 114:1439-45. 2001
    ..These molecules are activated by a variety of extracellular stimuli and have been implicated in a wide range of cellular processes, including cell cycle progression, cell growth, cell motility, cell adhesion and cell survival...
  80. ncbi Oncogenic kinase signalling
    P Blume-Jensen
    The Salk Institute, Molecular and Cell Biology Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
    Nature 411:355-65. 2001
    ....
  81. ncbi Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators
    Puvi N Seshiah
    Division of Cardiology, Emory University, Atlanta, GA 30322, USA
    Circ Res 91:406-13. 2002
    ....
  82. ncbi PI3K in lymphocyte development, differentiation and activation
    Klaus Okkenhaug
    Molecular Immunology Programme, The Babraham Institute, Cambridge CB2 4AT, UK
    Nat Rev Immunol 3:317-30. 2003
    ..Additional recent work has provided new insights into the molecular interactions that lead to PI3K activation and the signalling pathways that are regulated by PI3K...
  83. ncbi The CD28 signaling pathway regulates glucose metabolism
    Kenneth A Frauwirth
    Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
    Immunity 16:769-77. 2002
    ..These data suggest that CD28 costimulation functions to increase glycolytic flux, allowing T cells to anticipate energetic and biosynthetic needs associated with a sustained response...
  84. pmc Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)
    A Brunet
    Division of Neuroscience, Children s Hospital and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Mol Cell Biol 21:952-65. 2001
    ..These findings indicate that SGK acts in concert with Akt to propagate the effects of PI3K activation within the nucleus and to mediate the biological outputs of PI3K signaling, including cell survival and cell cycle progression...
  85. ncbi Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement
    Chanchal Sadhu
    ICOS Corporation, Bothell, WA 98021, USA
    J Immunol 170:2647-54. 2003
    ..These results demonstrate that PI3K delta can play a selective role in the amplification of PIP3 levels that lead to neutrophil polarization and directional migration...
  86. ncbi The regulation and function of Class III PI3Ks: novel roles for Vps34
    Jonathan M Backer
    Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
    Biochem J 410:1-17. 2008
    ..Thus Class III PI3Ks are implicated in the regulation of both autophagy and, through the mTOR pathway, protein synthesis, and thus contribute to the integration of cellular responses to changing nutritional status...
  87. ncbi PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas
    Jong Woo Lee
    Department of Pathology, College of Medicine, Catholic University of Korea, 505 Banpo Dong, Socho gu, Seoul 137 701, Korea
    Oncogene 24:1477-80. 2005
    ..The high incidence and wide distribution of PIK3CA gene mutation in the common human cancers suggest that alterations of lipid kinase pathway by PIK3CA mutations contribute to the development of human cancers...
  88. ncbi PI 3-kinase, Akt and cell survival
    Julian Downward
    Cancer Research UK London Research Institute, 44 Lincoln s Inn Fields, London WC2A 3PX, UK
    Semin Cell Dev Biol 15:177-82. 2004
    ..In addition, novel connections between the metabolic effects of Akt and its control of survival have recently been made...
  89. ncbi Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase
    L Bi
    Genetic Diseases Research Branch, NHGRI, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Biol Chem 274:10963-8. 1999
    ..A proliferative defect is supported by the observation that fibroblasts from Pik3cadel/del embryos fail to replicate in Dulbecco's modified Eagle's medium and fetal calf serum, even with supplemental growth factors...
  90. ncbi XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells
    E Asselin
    Department of Obstetrics and Gynaecology, University of Ottawa, Loeb Health Research Institute, The Ottawa Hospital, Ontario, Canada
    Cancer Res 61:1862-8. 2001
    ..These results demonstrate a novel mechanism by which XIAP regulates apoptosis and the possible involvement of the PI 3-K/Akt survival pathway in XIAP-mediated chemoresistance of ovarian cancer cells...
  91. ncbi Frequent mutation of the PIK3CA gene in ovarian and breast cancers
    Douglas A Levine
    Gynecology and Breast Research Laboratory, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    Clin Cancer Res 11:2875-8. 2005
    ..Here, we test whether PIK3CA is subject to mutation in ovarian and breast cancers...
  92. ncbi The mitogenic and myogenic actions of insulin-like growth factors utilize distinct signaling pathways
    S A Coolican
    Biology Department, Syracuse University, Syracuse, New York 13244, USA
    J Biol Chem 272:6653-62. 1997
    ..Thus, it appears that signaling from the IGF-I receptor utilizes two distinct pathways leading either to proliferation or differentiation...
  93. ncbi Structure and function of phosphoinositide 3-kinases
    M P Wymann
    Institute of Biochemistry, University of Fribourg, Rue du Musee 5, CH 1700 Fribourg, Switzerland
    Biochim Biophys Acta 1436:127-50. 1998
    ..Recent disruption of PI3K genes in slime mold, Caenorhabditis elegans, Drosophila melanogaster and mice further underlines the importance of PI3K signaling systems and elucidates the role of PI3K signaling in multicellular organisms...
  94. pmc An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice
    K Podsypanina
    Institute of Cancer Genetics, Department of Pathology and Medicine, College of Physicians and Surgeons, Columbia University, 1150 St Nicholas Avenue, Russ Berrie Pavilion, New York, NY 10032, USA
    Proc Natl Acad Sci U S A 98:10320-5. 2001
    ..These data suggest that p70/S6K and possibly other targets of mTOR contribute significantly to tumor development and that inhibition of these proteins may be therapeutic for cancer patients with deranged PI3K signaling...
  95. ncbi PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma
    Lao H Saal
    Integrated Program in Cellular, Molecular, and Biophysical Studies, Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA
    Cancer Res 65:2554-9. 2005
    ..Thus, mutation of PIK3CA is frequent, occurs early in carcinoma development, and has prognostic and therapeutic implications...
  96. ncbi Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells
    Steven J Isakoff
    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Cancer Res 65:10992-1000. 2005
    ..Together, these data support the notion that the cancer-associated mutations in PIK3CA may significantly contribute to breast cancer pathogenesis and represent attractive targets for therapeutic inhibition...
  97. pmc Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1
    W H Biggs
    The Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093 0660, USA
    Proc Natl Acad Sci U S A 96:7421-6. 1999
    ..These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus...
  98. ncbi Chemotaxis in shallow gradients is mediated independently of PtdIns 3-kinase by biased choices between random protrusions
    Natalie Andrew
    School of Biosciences, The University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
    Nat Cell Biol 9:193-200. 2007
    ....
  99. ncbi Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate
    T F Franke
    ABL Basic Research Program, National Cancer Institute Frederick Cancer Research Facility and Development Center NCI FCRFDC, Frederick, MD 21702, USA
    Science 275:665-8. 1997
    ..Thus, Akt is apparently regulated by the direct interaction of PtdIns-3,4-P2 with the Akt PH domain...
  100. ncbi Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance
    James A McCubrey
    Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
    Adv Enzyme Regul 46:249-79. 2006
    ..These signaling and anti-apoptotic pathways can have different effects on growth, prevention of apoptosis and induction of drug resistance in cells of various lineages which may be due to the expression of lineage-specific factors...
  101. ncbi Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies
    Jayne M Stommel
    Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
    Science 318:287-90. 2007
    ..Thus, effective GBM therapy may require combined regimens targeting multiple RTKs...

Research Grants70

  1. Novel TIRF microscopy analyzing trafficking & signaling at the cell cortex
    Derek Toomre; Fiscal Year: 2009
    ..Consistent with the recovery act's goal, this funding will provide full-time summer employment for 4 undergraduate students and accelerate scientific achievement of the parent DP2 award...
  2. Mechanism of Bladder Overactivity in Pelvic Ischemia
    Kazem M Azadzoi; Fiscal Year: 2013
    ..abstract_text> ..
  3. Role of Diabetes in Development of Renal Cell Carcinoma
    SAMY LEWIZ HABIB; Fiscal Year: 2013
    ....
  4. BONE MATRIX AND BONE RESORPTION
    Paul R Odgren; Fiscal Year: 2012
    ..This proposal aims to investigate new genes that regulate the formation and activity of osteoclasts to better understand bone biology in general, and potentially to find new ways to treat these widespread bone disorders. ..
  5. PTEN TUMOR SUPPRESSOR AND SIGNAL TRANSDUCTION
    RAMON E PARSONS; Fiscal Year: 2012
    ..09/04) Page 4 Form Page 3 ..
  6. Role of leptin-mediated PI3 Kinase signaling on reproductive control
    Carol Fuzeti Elias; Fiscal Year: 2013
    ..Obesity and diabetes can also negatively affect fertility. Thus, it is hoped that our studies may open new fronts for the understanding and for further treatment of reproductive deficits caused by metabolic dysfunctions. ..
  7. Extracellular ubiquitin: role in myocyte apoptosis and myocardial remodeling
    Krishna Singh; Fiscal Year: 2010
    ....
  8. Regulation of apoptosis by PI 3-kinase/Akt signaling
    Geoffrey M Cooper; Fiscal Year: 2012
    ..The present proposal seeks to further understand the mechanism by which this pathway regulates cell survival. Discoveries of novel targets of PI 3-kinase signaling may provide new targets for cancer treatment. ..
  9. The function of ATM protein in the biology of the adult neuron CNS:
    Karl Herrup; Fiscal Year: 2013
    ..The exploration of these phenomena will thus have significant value for our basic biological understanding of brain function as well as its malfunction in a number of different clinically relevant situations. ..
  10. Beta-cell Proliferation
    Fredric E Wondisford; Fiscal Year: 2013
    ..These studies of in vivo mechanisms of [unreadable]-cell proliferation may provide therapeutic approaches for diabetes mellitus in humans. ..
  11. Preclinical testing of a novel PDK1 inhibitor for treating vestibular schwannoma
    Abraham Jacob; Fiscal Year: 2013
    ..OSU-03012 may represent the first medical treatment alternative for patients afflicted with VS. ..
  12. Anthrax Toxins Impair Phagocyte Actin-based Motility
    Frederick Southwick; Fiscal Year: 2010
    ....
  13. Peptide Therapy for Pulmonary Arterial Hypertension
    Jawaharlal M Patel; Fiscal Year: 2013
    ..Confirmation of the mechanism-based physiological approach for NO releasing PDE5 inhibitor function of this novel peptide in preclinical animal model is innovative for progression towards Phase I clinical trial for treatment of PH. ..
  14. Gq-coupled Receptors Inhibit PI 3-kinase/Akt Signaling Pathway
    Richard Z Lin; Fiscal Year: 2012
    ..Moreover, systemic inhibition of PI3K runs the risk of adverse side effects if these enzymes play important roles in regulating organ function, including maintenance of muscle mass. ..
  15. MOLECULAR MODELS OF IMMUNE-MEDIATED VASCULAR INJURY
    Jeffrey R Bender; Fiscal Year: 2012
    ....
  16. MECHANISM OF RETROCORNEAL FIBROUS MEMBRANE
    EunDuck P Kay; Fiscal Year: 2010
    ..Such detailed information is crucial for targeting the specific stage and specific pathway before inflammation causes an irreversible EMT. ..
  17. Phosphoprotein CDP138 regulates glucose metabolism
    ZHEN YUE JIANG; Fiscal Year: 2013
    ..Together, this project will provide valuable and novel insight into the molecular mechanisms by which CDP138 acts as a point of convergence between kinase activation and glucose transport. ..
  18. Regulation of Neuronal Survival by the Rit GTPase
    DOUGLAS ALLEN ANDRES; Fiscal Year: 2012
    ..Thus, the goal of this research is to speed progress toward therapeutic exploitation of this protein in neurodegenerative disease. ..
  19. Oncogenic Kit receptor signaling in vivo
    Peter Besmer; Fiscal Year: 2012
    ..Furthermore we will produce and characterize mice carrying oncogenic imatinib resistant Kit alleles. ..
  20. Chemokine Signals in the Premetastatic Niche Inhibit Metastasis
    Ann Richmond; Fiscal Year: 2013
    ....
  21. The p110 alpha and delta isoforms of PI3 kinase in hematopoiesis and leukemia
    Kira Gritsman; Fiscal Year: 2013
    ..This proposal will use mouse knockout models to examine whether the p110 and p110 subunits of PI3 kinase are important for normal HSC function and are feasible targets for leukemia therapy. ..
  22. Physiology of Class III PI 3-kinase Signaling 2
    Jonathan M Backer; Fiscal Year: 2013
    ..Given that hVps34 is one of the key kinases involved in autophagy, a better understanding of its regulation will lead to new insights into this critical cellular process. ..
  23. Arrestin Regulation of CRF1 Signaling: Mechanisms for Stress Resilience and PTSD
    Richard L Hauger; Fiscal Year: 2013
    ..We will also direct our research toward identifying novel molecular targets for drug discovery that will lead to new PTSD treatments with higher efficacy and therapeutic index. ..
  24. Vascular Phenotypic Regulation by Growth Factors, Insulin and Glucose
    Lakshman Segar; Fiscal Year: 2011
    ..Strategies to inhibit PDGF receptor signaling may prevent dysregulated glucose metabolism and insulin signaling to improve vascular function in nondiabetic and diabetic patients. ..
  25. Coordinate Regulation Of Nuclear DGK-theta and PLD
    DANIEL RABEN; Fiscal Year: 2009
    ..We believe that an understanding of nuclear lipid signaling is key to our ability to intervene in events such as wound repair and tissue remodeling. ..
  26. Mechanisms of Anti-fungal Vaccine Immunity
    BRUCE STEVEN KLEIN; Fiscal Year: 2013
    ..It breaks new ground about anti-fungal memory immunity in CD4 deficient hosts, the role of Tc17 cells, and how these cells develop and their developmental pathways can be harnessed by adjuvant to protect immune deficient patients. ..
  27. Focal Adhesion Kinase - Tumor Biology and Therapeutics
    William G Cance; Fiscal Year: 2013
    ..Thus, this application will provide novel molecular cancer therapeutics that target the focal adhesion kinase. ..
  28. Novel Molecules in Calcium Signaling in Platelets
    Wolfgang Bergmeier; Fiscal Year: 2013
    ..An in-depth analysis of how CD-GEFI regulates platelet function in vitro and in vivo will aid in its establishment as a target for antiplatelet therapy. ..
  29. Signaling pathways regulated by GSK3 in hematopoietic stem cell
    Jian Huang; Fiscal Year: 2012
    ..The long-term goals of this project are to extend our understanding of HSC biology and to improve HSC/bone marrow transplantation. ) ..
  30. BDNF-Trk Signaling &Cytokines in Patients with Mood Disorders
    Ghanshyam N Pandey; Fiscal Year: 2013
    ..Abnormalities of BDNF and HPA axis have been observed in patients with MD. This research will investigate BDNF-mediated signaling pathways and mechanisms of HPA dysfunction. ..
  31. Notch-1 and IGF-1 crosstalk: new therapeutic strategies for NSCLC
    Maurizio Bocchetta; Fiscal Year: 2013
    ..Furthermore, the study will test the clinical usefulness of targeting Notch signaling to treat NSCLC using GSI. Finally, these experiments will elucidate the role of Notch-1 in lung tumorigenicity in vitro and in vivo. ..
  32. Targeting crosstalk between insulin and Gq signaling systems in pancreatic cancer
    JUAN ENRIQUE ROZENGURT; Fiscal Year: 2010
    ....
  33. PTEN Gene Therapy for Vein Graft Disease
    Christopher D Kontos; Fiscal Year: 2010
    ..The results of these studies may have a substantial impact on outcomes for patients requiring venous bypass grafting and AVF placement. ..
  34. Redox Regulation of p21ras in Angiogenesis
    Richard A Cohen; Fiscal Year: 2013
    ..By understanding the molecular mechanisms by which angiogenesis is normally redox-regulated by p21ras and GRX1, we anticipate being able to determine why angiogenesis is impaired in metabolic disease. ..
  35. Cancer cell signaling through lipids complexed to proteins
    RAYMOND DANIEL BLIND; Fiscal Year: 2013
    ..The candidate will expand his research program as an independent investigator with the training afforded by this K01 award, opening new avenues to cancer research. ..
  36. DC-T Cell Interactions in Pulmonary Immune Responses
    Anuradha Ray; Fiscal Year: 2012
    ..These studies will help identify targets for inhibiting undesired immune responses in the lung at the same time promoting those that protect from infectious agents. ..
  37. A forward genetics screen for genes regulating phagocytosis and signaling in Enta
    Lesly A Temesvari; Fiscal Year: 2010
    ..Since these cellular processes are important to E. histolytica virulence, this work will significantly enhance our understanding of pathogenicity. ..
  38. Antibody-interferon fusion proteins for treatment of B-cell malignancies
    Sherie L Morrison; Fiscal Year: 2013
    ..B. Evaluate the in vivo efficacy of the fusion proteins against human lymphoma xenografts in combination with inhibitors of mTOR (temsirolimus) or PI3 kinase d (CAL-120). ..
  39. Paraventricular Nucleus Signaling Mechanisms in Hypertension
    Carrie A Northcott; Fiscal Year: 2010
    ..In addition, due to the integrative nature of the PVN, these data will also provide a glimpse at the role of signaling in other physiological conditions, such as obesity. ..
  40. Determinants of Germinal Center B Cell Differentiation
    Robert C Rickert; Fiscal Year: 2013
    ..Such knowledge will be of direct relevance for the application of small molecular therapeutics to enhance (e.g. for vaccines) or inhibit (e.g. in autoimmunity) the PI3-kinase pathway in specific settings. ..
  41. Macrophage-lipoprotein interactions
    Frederick R Maxfield; Fiscal Year: 2013
    ..Such insights may help in developing therapies as well as providing deeper understanding of the underlying basis for cardiovascular risk factors such as elevated biomarkers for inflammation. ..
  42. Targeting the ARF/CtBP Axis in Pancreatic Cancer
    Steven R Grossman; Fiscal Year: 2010
    ....
  43. Extranuclear estrogen receptor actions on endometrial cancer cell proliferation
    Twila A Jackson; Fiscal Year: 2012
    ..Understanding novel mechanisms of estrogen receptor action may provide new targets for endocrine therapies. ..
  44. Dysregulation of mTOR Signaling in Fragile X Syndrome
    R Suzanne Zukin; Fiscal Year: 2013
    ..These translational studies will create a foundation for generating novel therapeutic strategies to ameliorate this serious human condition. ..
  45. Role of lipid rafts and phosphoinositides in E. histolytica virulence
    Lesly A Temesvari; Fiscal Year: 2010
    ..Since signaling likely regulates virulence, these studies will contribute significantly to understanding the biology of E. histolytica. ..
  46. Role of serum- and glucocorticoid-regulated kinase-1 in electrical remodeling
    Anthony Rosenzweig; Fiscal Year: 2013
    ..Thus understanding SGK1's role in the heart could have important practical implications, and the current application would help advance our understanding of the potential of SGK1 as a therapeutic target. ..
  47. Regulating IRS1 by Ser/Thr Phosphorylation
    Morris F White; Fiscal Year: 2013
    ..3. Identify the mTORC1-dependent phosphorylation sites in IRS1 that regulate insulin signaling and glucose tolerance in mice. ..
  48. Cellular Determinants of Apoptosis in Virus-Infected Cells
    Ganes C Sen; Fiscal Year: 2012
    ..For this purpose, the different steps of the viral life cycle will be examined. Moreover, the status of the innate immune response in the persistently infected cells will be evaluated. ..
  49. Mechanism of Renal Cell Injury
    Goutam Ghosh Choudhury; Fiscal Year: 2013
    ....
  50. Regulation of cyclin D3 in B lymphocyte development
    Marcus R Clark; Fiscal Year: 2013
    ..These studies will lead to a greater understanding of both the generation of the immune system of those processes that lead to leukemia. ..
  51. Oxidative Stress and the Development of Osteoarthritis
    Richard F Loeser; Fiscal Year: 2013
    ....
  52. Novel Determinants of Terminal Erythroid Maturation
    Saghi Ghaffari; Fiscal Year: 2013
    ..Given the importance of GATA and FoxO factors for regulating diverse processes, the studies will yield broad mechanistic and biological insights. (End of Abstract) ..
  53. Molecular Regulation and Biological Functions of PIKE-A
    Keqiang Ye; Fiscal Year: 2012
    ..The proposed study is expected to provide insight into the function of PIKE-A in cancer biology. Accomplishing these aims will lead to development of drugs for curing of cancers. ..
  54. TGF-beta-induced non-Smad signaling events and cancer cell behavior
    RIK M DERYNCK; Fiscal Year: 2013
    ..This knowledge is likely to provide new and more selective avenues than hitherto possible to block the invasive and metastatic behavior of cancers. ..
  55. Cellular Determinants of Apoptosis in Virus-Infected Cells
    Ganes C Sen; Fiscal Year: 2013
    ..Finally, genetically modified mice, including new IRF-3 mutant knock-in mice which have been generated for this project, will be used to assess the in vivo contribution of RIPA in controlling viral pathogenesis. ..
  56. INSULIN SIGNALING DEFECTS IN PCOS
    Ricardo Azziz; Fiscal Year: 2010
    ..Moreover, we anticipate that by advancing the rate of our existing research, the supplement will enable us to lay the foundations for future submissions, which has the potential to both secure existing jobs and create new ones ..
  57. Signaling pathways regulated by GSK3 in hematopoietic stem cell
    Jian Huang; Fiscal Year: 2013
    ..The knowledge learned from these studies will provide new insights into the mechanisms of the regulation of HSC self-renewal and differentiation and may improve the therapy of hematopoietic disorders. 1 ..
  58. SGK1 is a Central Regulator of P. gingivalis-Induced Inflammation
    Huizhi Wang; Fiscal Year: 2013
    ....
  59. Targeted Therapy for Lymphoid Malignancies
    AMY JO JOHNSON; Fiscal Year: 2013
    ..These will guide future combination studies with Ibrutinib that has great potential to completely change the treatment paradigm of CLL. ..
  60. Caveolin-1 and NO Regulate PMN-mediated Increases in Vascular Permeability
    Richard D Minshall; Fiscal Year: 2011
    ....
  61. Adipocyte insulin signaling and circulating adiponectin levels
    ROCIO INES PEREIRA; Fiscal Year: 2010
    ..The anticipated results of this clinical study may provide new insight into potential therapeutic targets in patients with T2DM, obesity, and MetS. ..
  62. Erythropoietin PLUS IGF-IN NEUROPROTECTION FROM AIDS
    Stuart Lipton; Fiscal Year: 2009
    ..Hypothesis Tested: EPO+IGF-I act synergistically to activate the anti-apoptotic PI3 kinase/Akt signaling pathway, and thus provide a synergistic degree of neuroprotection. ..
  63. REGULATION OF PLASMA CELL MALIGNANCY BY INSULIN AND IGF
    GREGORY FREUND; Fiscal Year: 2000
    ..Freund has a unique opportunity to develop into an outstanding clinician and scientist. ..
  64. Quercetin Treatment of Airway Inflammation
    MARC HERSHENSON; Fiscal Year: 2006
    ..This project examines the value of quercetin, a plant pigment, in preventing airway inflammation in mouse models of disease. This work may lead to new treatments for asthma, cystic fibrosis or chronic bronchitis. ..
  65. Ras and Chemokine Stimulated Neutrophil Polarization
    Cindy Knall; Fiscal Year: 2004
    ..The proposed study fulfills the scope of the NIAID small research grants program as a small, self-contained research project requiring minimal funding for a limited time. ..
  66. Mechansim of tea catechin's inhibition of angiogenesis
    Mohsen Meydani; Fiscal Year: 2003
    ..abstract_text> ..
  67. Insulin Signaling to GLUT4 and the Actin Cytoskeleton
    Michael Czech; Fiscal Year: 2007
    ..Together, these experiments will clarify the role of Myo1c and the actin cytoskeleton in GLUT4 regulation by insulin. ..
  68. DETERMINANTS OF TISSUE ESTRADIOL SENSITIVITY
    Richard Santen; Fiscal Year: 2009
    ..FTS, a novel mTOR inhibitor will be used in vitro to activate the stress kinase pathway and apoptosis. In vivo, FTS will be used to enhance estradiol induced apoptosis in nude mice. ..
  69. Role of PI3K in Sepsis-induced Acute Lung Injury
    Gary Hunninghake; Fiscal Year: 2006
    ..Therefore, the overall hypothesis of this project is that PI 3-kinase activity is a molecular switch that regulates the transition from production of pro- (TNF) to anti- (PGE2) inflammatory mediators. ..
  70. Role of Ras Effectors in Mammary Differentiation
    MARY CUTLER; Fiscal Year: 2004
    ..The research proposed here will determine the mechanism by which an important mitogenic signal transduction pathway, which is frequently activated in breast carcinoma, inhibits mammary differentiation and apoptosis. ..