DISSECTION OF STRESS SIGNALING PATHWAYS TO A MAP KINASE

Summary

Principal Investigator: K Shiozaki
Affiliation: University of California
Country: USA
Abstract: An ability to sense and respond to diverse stress stimuli from the environment is a basic cellular function conserved throughout evolution. In unicellular organisms, such responses are critical for survival. In higher organisms including humans, cellular stress responses can be seen in the inflammation resulting from asthma, arthritis, or bacterial infection, as well as in the response of cancer cells to cytotoxic therapies. In order to sense stress stimuli and regulate cellular physiology, eukaryotic organisms from yeast to humans utilize a signaling module called a MAP kinase (MAPK) cascade. MAPKs dedicated for stress signaling are also known as SAPKs (Stress-Activated Protein Kinases) and play key roles in cellular responses to changes in the environmental conditions as well as responses to bacterial endotoxins, inflammatory cytokines, and chemotherapeutic drugs. The long-term objective of the research described in this proposal is to understand at a molecular level how diverse stress stimuli are sensed and transmitted to SAPK, and how activated SAPK then modulates cellular processes for stress adaptation. These studies will use the genetically tractable model system provided by the fission yeast Schizosaccharomyces pombe, whose SAPK pathway has been demonstrated to be structurally and functionally similar to those in humans. Signaling within MAPK cascades is achieved by sequential activation of a MAPK kinase kinase (MAPKKK), a MAPK kinase (MAPKK) and finally, a MAPK. In the S. pombe SAPK cascade, signaling to the Spcl SAPK is initiated by two MAPKKKs, Wis4 and Win1. We have found that Wis4 and Win1 form a complex with multiple proteins and serve as a hub for stress sensing and response via the Spc1 pathway. The three specific aims focus on this MAPKKK complex: (I) to determine how the complex is organized and discover novel proteins that interact with Wis4 and Win1; (II) to uncover how oxidative stress signaling to the SAPK cascade is mediated by a glycolytic enzyme, GAPDH, which has unexpectedly been found as a component of the MAPKKK complex; and (iii) to determine how another MAPKKK-interacting protein, Wsh3, regulates a newly discovered cellular function of the SAPK pathway, the maintenance of cell polarity under high similarity stress. It is anticipated that the proposed SAPK research in S. pombe will serve as a valuable paradigm for human SAPK, facilitating understanding of the roles of SAPKs in clinical contexts.
Funding Period: 1999-08-01 - 2008-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Yeast signaling pathways in the oxidative stress response
    Aminah Ikner
    Section of Microbiology, Division of Biological Sciences, University of California, Davis, CA 95616, USA
    Mutat Res 569:13-27. 2005
  2. pmc Response of fission yeast to toxic cations involves cooperative action of the stress-activated protein kinase Spc1/Sty1 and the Hal4 protein kinase
    Ling yu Wang
    Section of Microbiology, Division of Biological Sciences, University of California, Davis, CA 95616, USA
    Mol Cell Biol 25:3945-55. 2005
  3. ncbi Wsh3/Tea4 is a novel cell-end factor essential for bipolar distribution of Tea1 and protects cell polarity under environmental stress in S. pombe
    Hisashi Tatebe
    Section of Microbiology, Division of Biological Sciences, University of California, Davis, Davis, California 95616, USA
    Curr Biol 15:1006-15. 2005
  4. ncbi The fission yeast stress MAPK cascade regulates the pmp3+ gene that encodes a highly conserved plasma membrane protein
    Ling yu Wang
    Section of Microbiology, College of Biological Sciences, University of California, One Shields Avenue, Davis, CA 95616, USA
    FEBS Lett 580:2409-13. 2006
  5. pmc Fission yeast TOR complex 2 activates the AGC-family Gad8 kinase essential for stress resistance and cell cycle control
    Kyoko Ikeda
    Section of Microbiology, College of Biological Sciences, University of California, Davis, California, USA
    Cell Cycle 7:358-64. 2008
  6. pmc Pom1 DYRK regulates localization of the Rga4 GAP to ensure bipolar activation of Cdc42 in fission yeast
    Hisashi Tatebe
    Section of Microbiology, College of Biological Sciences, University of California, Davis, California 95616, USA
    Curr Biol 18:322-30. 2008
  7. pmc Glycolytic enzyme GAPDH promotes peroxide stress signaling through multistep phosphorelay to a MAPK cascade
    Susumu Morigasaki
    Department of Microbiology, College of Biological Sciences, University of California, Davis, Davis, CA 95616, USA
    Mol Cell 30:108-13. 2008

Detail Information

Publications7

  1. ncbi Yeast signaling pathways in the oxidative stress response
    Aminah Ikner
    Section of Microbiology, Division of Biological Sciences, University of California, Davis, CA 95616, USA
    Mutat Res 569:13-27. 2005
    ..The structure and function of these signaling modules are discussed...
  2. pmc Response of fission yeast to toxic cations involves cooperative action of the stress-activated protein kinase Spc1/Sty1 and the Hal4 protein kinase
    Ling yu Wang
    Section of Microbiology, Division of Biological Sciences, University of California, Davis, CA 95616, USA
    Mol Cell Biol 25:3945-55. 2005
    ..Interestingly, the Spc1-Hal4 interaction appears to be required for cellular resistance to Ca(2+) but not Na(+) and Li(+). We propose that Spc1 SAPK and Hal4 kinase cooperatively function to protect cells from the toxic cations...
  3. ncbi Wsh3/Tea4 is a novel cell-end factor essential for bipolar distribution of Tea1 and protects cell polarity under environmental stress in S. pombe
    Hisashi Tatebe
    Section of Microbiology, Division of Biological Sciences, University of California, Davis, Davis, California 95616, USA
    Curr Biol 15:1006-15. 2005
    ..The deltatea1 mutant cells cannot grow in a bipolar fashion and show T-shaped morphology after heat shock...
  4. ncbi The fission yeast stress MAPK cascade regulates the pmp3+ gene that encodes a highly conserved plasma membrane protein
    Ling yu Wang
    Section of Microbiology, College of Biological Sciences, University of California, One Shields Avenue, Davis, CA 95616, USA
    FEBS Lett 580:2409-13. 2006
    ..Transcriptional regulation of the Pmp3-like genes by the stress-activated MAPK may also be conserved in other eukaryotes, including plants...
  5. pmc Fission yeast TOR complex 2 activates the AGC-family Gad8 kinase essential for stress resistance and cell cycle control
    Kyoko Ikeda
    Section of Microbiology, College of Biological Sciences, University of California, Davis, California, USA
    Cell Cycle 7:358-64. 2008
    ..These results strongly suggest that the TORC2-Gad8 pathway has multiple physiological functions in cellular stress resistance and cell cycle progression at both G(1)/S and G(2)/M transitions...
  6. pmc Pom1 DYRK regulates localization of the Rga4 GAP to ensure bipolar activation of Cdc42 in fission yeast
    Hisashi Tatebe
    Section of Microbiology, College of Biological Sciences, University of California, Davis, California 95616, USA
    Curr Biol 18:322-30. 2008
    ..Pom1 is required for proper positioning of growth sites, and the Deltapom1 mutation brings about monopolar cell growth...
  7. pmc Glycolytic enzyme GAPDH promotes peroxide stress signaling through multistep phosphorelay to a MAPK cascade
    Susumu Morigasaki
    Department of Microbiology, College of Biological Sciences, University of California, Davis, Davis, CA 95616, USA
    Mol Cell 30:108-13. 2008
    ..These results demonstrate that the glycolytic enzyme GAPDH plays an essential role in the phosphorelay signaling, where its redox-sensitive cysteine residue may provide additional input signals...