Cytokine signal transduction in immune system

Summary

Principal Investigator: Hodaka Fujii
Abstract: Signal transduction from type I and type II cytokine receptors plays important roles in development and function of cells regulating immune system. Although accumulating evidence suggests importance of Jak-Stat pathways in cytokine signal transduction, our earlier studies and other reports demonstrated that lymphocytes can differentiate and function even in the absence of the activation of Stat proteins, leading to a hypothesis that Stat-independent signaling pathways may play important roles in lymphocyte differentiation and function. However, the molecular nature of Stat-independent pathways is still elusive. The objective of the present research is to elucidate these elusive signaling pathways by using a novel expression cloning system, inducible translocation trap (ITT). ITT is based on translocation of a fusion protein consisting of LexA DNA-binding domain, transactivation domain of a strong transcriptional activator and a test molecule. LexA-mediated reporter gene expression is detected by flow cytometry. This system will be employed to analyze Stat-independent pathways in interferon gamma, as well as interleukin (IL)-2 and IL-3 signaling. The initial screening of cDNA library revealed that an isoform of pyruvate kinase (M2-PK), a key enzyme in glycolysis, translocates into the nucleus following IL-3 stimulation. In addition, it was found that the nuclear M2-PK plays an important role in cell proliferation. Molecular mechanisms of IL-3-induced nuclear translocation of M2-PK and enhancement of cell proliferation by the nuclear M2-PK will be analyzed by using molecular and cell biological techniques. Detailed information gained from the proposed experiments will be valuable for elucidation of molecular mechanisms of oncogenesis and autoimmune diseases caused by dysregulation of cytokine signaling.
Funding Period: 2004-12-01 - 2007-11-30
more information: NIH RePORT

Top Publications

  1. pmc Regulation of Stat1 protein expression by phenylalanine 172 in the coiled-coil domain
    Akemi Hoshino
    Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
    Biochem Biophys Res Commun 346:1062-6. 2006
  2. pmc Regulation of Fas-mediated immune homeostasis by an activation-induced protein, Cyclon
    Shella Saint Fleur
    Department of Pathology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, USA
    Blood 114:1355-65. 2009
  3. pmc Lack of nuclear translocation of cytoplasmic domains of IL-2/IL-15 receptor subunits
    Hodaka Fujii
    Department of Pathology, New York University School of Medicine, 550 First Avenue, MSB 126, NY 10016, USA
    Cytokine 46:302-8. 2009
  4. pmc Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression
    Rui Wang
    Department of Microbiology, New York University School of Medicine, New York, New York, United States of America
    PLoS ONE 3:e2705. 2008
  5. pmc Cytokine-induced nuclear translocation of signaling proteins and their analysis using the inducible translocation trap system
    Shella Saint Fleur
    Department of Pathology, New York University School of Medicine, 550 First Avenue, MSB 126, New York, NY 10016, USA
    Cytokine 41:187-97. 2008
  6. ncbi Plasmodium circumsporozoite protein promotes the development of the liver stages of the parasite
    Agam Prasad Singh
    Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
    Cell 131:492-504. 2007
  7. pmc Nuclear translocation of 2-amino-3-ketobutyrate coenzyme A ligase by cold and osmotic stress
    Akemi Hoshino
    Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
    Cell Stress Chaperones 12:186-91. 2007
  8. pmc Temporal regulation of Stat5 activity in determination of cell differentiation program
    Akemi Hoshino
    Department of Pathology, New York University School of Medicine, 550 First Avenue, MSB 126, New York, NY 10016, USA
    Biochem Biophys Res Commun 358:914-9. 2007
  9. ncbi Regulation of cell proliferation by interleukin-3-induced nuclear translocation of pyruvate kinase
    Akemi Hoshino
    Department of Pathology, New York University School of Medicine, New York, New York 10016, USA
    J Biol Chem 282:17706-11. 2007
  10. pmc Redundant promoter elements mediate IL-3-induced expression of a novel cytokine-inducible gene, cyclon
    Akemi Hoshino
    Department of Pathology, New York University School of Medicine, 550 First Avenue, MSB 126, New York, NY 10016, USA
    FEBS Lett 581:975-80. 2007

Scientific Experts

Detail Information

Publications12

  1. pmc Regulation of Stat1 protein expression by phenylalanine 172 in the coiled-coil domain
    Akemi Hoshino
    Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
    Biochem Biophys Res Commun 346:1062-6. 2006
    ..These results suggest a novel potential mechanism of determination of specificity of Stat proteins and showed that the ITT system is a powerful technique to identify mutants of nuclear translocating signal transducers...
  2. pmc Regulation of Fas-mediated immune homeostasis by an activation-induced protein, Cyclon
    Shella Saint Fleur
    Department of Pathology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, USA
    Blood 114:1355-65. 2009
    ..We think that our data provide insight into expression regulation of Fas in T cells...
  3. pmc Lack of nuclear translocation of cytoplasmic domains of IL-2/IL-15 receptor subunits
    Hodaka Fujii
    Department of Pathology, New York University School of Medicine, 550 First Avenue, MSB 126, NY 10016, USA
    Cytokine 46:302-8. 2009
    ..Collectively, these results indicated that potential nuclear function of cleaved type I cytokine receptor subunits is not plausible...
  4. pmc Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression
    Rui Wang
    Department of Microbiology, New York University School of Medicine, New York, New York, United States of America
    PLoS ONE 3:e2705. 2008
    ..These findings reveal a novel cell surface molecule-mediated regulatory mechanism, with implications for modulating aberrant immune responses...
  5. pmc Cytokine-induced nuclear translocation of signaling proteins and their analysis using the inducible translocation trap system
    Shella Saint Fleur
    Department of Pathology, New York University School of Medicine, 550 First Avenue, MSB 126, New York, NY 10016, USA
    Cytokine 41:187-97. 2008
    ..Finally, analysis of "nuclear translocatome", the entire set of proteins that translocate into or out of the nucleus in response to extracellular stimuli, by ITT is discussed...
  6. ncbi Plasmodium circumsporozoite protein promotes the development of the liver stages of the parasite
    Agam Prasad Singh
    Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
    Cell 131:492-504. 2007
    ..The presence of CS in the hepatocyte enhances parasite growth of the liver stages in vitro and in vivo. These findings have far reaching implications for drug and vaccine development against the liver stages of the malaria parasite...
  7. pmc Nuclear translocation of 2-amino-3-ketobutyrate coenzyme A ligase by cold and osmotic stress
    Akemi Hoshino
    Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
    Cell Stress Chaperones 12:186-91. 2007
    ..A large region of KBL was required for stress-induced nuclear translocation. The KBL reporter system will be a useful tool for the investigation of cold and osmotic stress responses...
  8. pmc Temporal regulation of Stat5 activity in determination of cell differentiation program
    Akemi Hoshino
    Department of Pathology, New York University School of Medicine, 550 First Avenue, MSB 126, New York, NY 10016, USA
    Biochem Biophys Res Commun 358:914-9. 2007
    ..The acidic region of the IL-2 receptor beta-chain was essential for this inhibition. These results underscore the importance of temporal regulation of Stat activity for regulation of cytokine-specific cell differentiation...
  9. ncbi Regulation of cell proliferation by interleukin-3-induced nuclear translocation of pyruvate kinase
    Akemi Hoshino
    Department of Pathology, New York University School of Medicine, New York, New York 10016, USA
    J Biol Chem 282:17706-11. 2007
    ....
  10. pmc Redundant promoter elements mediate IL-3-induced expression of a novel cytokine-inducible gene, cyclon
    Akemi Hoshino
    Department of Pathology, New York University School of Medicine, 550 First Avenue, MSB 126, New York, NY 10016, USA
    FEBS Lett 581:975-80. 2007
    ..A novel transient reporter assay revealed that mouse cyclon promoter contains redundant elements for IL-3-induced gene expression...
  11. pmc Cell type-specific roles of Jak3 in IL-2-induced proliferative signal transduction
    Hodaka Fujii
    Department of Pathology, New York University School of Medicine, 550 First Avenue, MSB 126, New York, NY 10016, USA
    Biochem Biophys Res Commun 354:825-9. 2007
    ..These data suggest a critical role of Jak3 in IL-2 signaling in the fibroblast cell line and may provide further insight into the cell type-specific mechanism of cytokine signaling...
  12. pmc Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells
    Rui Wang
    Department of Microbiology, NYU Cancer Institute and New York University School of Medicine, New York, NY 10016, USA
    Proc Natl Acad Sci U S A 106:13439-44. 2009
    ..Our findings highlight the significance of GARP both in dissecting duality of Treg/Th17 cell differentiation and as a marker to identify bona fide Tregs during diseases with chronic immune activation...