Eukaryotic cells from yeasts to human utilize multiple MAP kinase (MAPK) cascades to transmit diverse extracellular stimuli to the nucleus. Among these are MAPKs dedicated for stress signaling, which are also called SAPKs (Stress-Activated Protein Kinases). Accumulating evidence strongly suggests that the functions of human SAPKs are of clinical importance, especially in control of cell death and proliferation, the inflammation response and cell differentiation. In addition, SAPKs appear to be key determinants of the response of tumor cells to cytotoxic treatments and chemotherapeutic drugs. The long-term objective of the proposed research is to attain a comprehensive understanding of SAPK regulation in response to cytotoxic stress stimuli, an understanding which is crucial to the control of SAPKs in the clinical context. These studies will be carried out in the genetically tractable model system provided by the fission yeast Schizosaccharomyces pombe. This organism has been used successfully for discovering and analyzing basic biological mechanisms that are conserved among eukaryotes. Our previous studies have demonstrated that both the structure and function of the SAPK pathways are highly conserved between fission yeast and human. Particular aspects of this conservation which are important for this proposal include the facts that in both organisms the SAPK pathways respond to multiple and diverse stresses and control the activity of an ATF transcription factor. Therefore, general principles of SAPK regulation and stress signaling in eukaryotes should emerge from the proposed research. The goal of this project is to elucidate the mechanisms which transmit diverse environmental stress signals to the S. pombe SAPK, Spc1.
The specific aims focus on key upstream components of the Spc1 pathway, including the Wis1 MEK, the Wis4/Win1 MEKKs, and Mcs4, a homolog of the """"""""response regulator"""""""" member of bacterial two-component systems. Genetic and biochemical experiments will determine how MEKKs and the two-component signaling system regulate the Wis1 MEK in response to diverse stresses, including osmostress, oxidative stress, heat shock and UV irradiation. Additional regulatory mechanisms independent of Wis4/Win1 and Mcs4 will also be sought by genetic screens. Lastly, recent experiments strongly suggest that the Pyp1 and Pyp2 tyrosine phosphatases, which negatively regulate the Spcl SAPK, are directly involved in heat stress signaling to Spc1. This mechanism will be investigated in detail.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059788-05
Application #
6616110
Study Section
Molecular Biology Study Section (MBY)
Program Officer
Anderson, Richard A
Project Start
1999-08-01
Project End
2004-08-31
Budget Start
2003-08-01
Budget End
2004-08-31
Support Year
5
Fiscal Year
2003
Total Cost
$213,717
Indirect Cost
Name
University of California Davis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Morigasaki, Susumu; Ikner, Aminah; Tatebe, Hisashi et al. (2013) Response regulator-mediated MAPKKK heteromer promotes stress signaling to the Spc1 MAPK in fission yeast. Mol Biol Cell 24:1083-92
Morigasaki, Susumu; Shiozaki, Kazuhiro (2010) Two-component signaling to the stress MAP kinase cascade in fission yeast. Methods Enzymol 471:279-89
Tatebe, Hisashi; Shiozaki, Kazuhiro (2010) Rab small GTPase emerges as a regulator of TOR complex 2. Small GTPases 1:180-182
Tatebe, Hisashi; Morigasaki, Susumu; Murayama, Shinichi et al. (2010) Rab-family GTPase regulates TOR complex 2 signaling in fission yeast. Curr Biol 20:1975-82
Shiozaki, Kazuhiro (2009) Nutrition-minded cell cycle. Sci Signal 2:pe74
Ikeda, Kyoko; Morigasaki, Susumu; Tatebe, Hisashi et al. (2008) Fission yeast TOR complex 2 activates the AGC-family Gad8 kinase essential for stress resistance and cell cycle control. Cell Cycle 7:358-64
Tatebe, Hisashi; Nakano, Kentaro; Maximo, Rachel et al. (2008) Pom1 DYRK regulates localization of the Rga4 GAP to ensure bipolar activation of Cdc42 in fission yeast. Curr Biol 18:322-30
Morigasaki, Susumu; Shimada, Koichi; Ikner, Aminah et al. (2008) Glycolytic enzyme GAPDH promotes peroxide stress signaling through multistep phosphorelay to a MAPK cascade. Mol Cell 30:108-13
Wang, Ling-yu; Shiozaki, Kazuhiro (2006) The fission yeast stress MAPK cascade regulates the pmp3+ gene that encodes a highly conserved plasma membrane protein. FEBS Lett 580:2409-13
Wang, Ling-Yu; Shimada, Koichi; Morishita, Masayo et al. (2005) Response of fission yeast to toxic cations involves cooperative action of the stress-activated protein kinase Spc1/Sty1 and the Hal4 protein kinase. Mol Cell Biol 25:3945-55

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