To maximize the probability of survival, unicellular organisms, such as yeast, have elaborate mechanisms to sense stressful environments and modulate their growth and metabolism accordingly. Although cells in multicellular organisms are exposed to less environmental fluctuation, the stress response mechanisms are conserved also in animals and play pivotal roles in cellular homeostasis. Among those mechanisms are intracellular signaling pathways known as the stress-activated protein kinase (SAPK) cascade and the TOR (target of rapamycin) pathways. They are implicated in the pathology of numerous human diseases, including cancers, inflammatory conditions and metabolic syndromes, where cellular homeostasis is disturbed by genetic disorders, infection and other etiologic agents. Therefore, elucidating the regulation and interplay of these signaling pathways have broad implications for improving human health. The long-term objective of the research described in this proposal is to understand at a molecular level the crosstalk between the SAPK cascade and the TOR complex 2 (TORC2) signaling pathway, both of which control cellular response to stressful environments. The studies will utilize the genetically amenable model system provided by the fission yeast Schizosaccharomyces pombe, which has SAPK and TORC2 pathways highly homologous to those in humans. Furthermore, in both fission yeast and humans, an essential TORC2 component, Sin1, has been found to interact with SAPK, possibly serving as a molecular link between the two signaling pathways. The three specific aims of the proposal focus on protein-protein interactions that mediate signaling within and between the SAPK and TORC2 pathways. The first is to understand how two MAPK kinase kinases (MAPKKKs) in the SAPK cascade form a heteromer complex and how the MAPKKK complex is regulated upon stress.
The second aim i s to determine how the interaction of SAPK with the Sin1 protein modulates TORC2 activity.
The third aim i s to discover how proteins interacting with Sin1 regulate TORC2 in response to extracellular stimuli. It is anticipated that the findings from these studies will serve as an invaluable paradigm for the investigation of the human SAPK and TORC2 pathways, facilitating understanding of their interplay in clinical contexts.

Public Health Relevance

Cells have evolutionarily conserved mechanisms to monitor the environment and modulate their growth and metabolism accordingly. This research utilizes fission yeast as a genetically amenable model to study the regulation and interaction of such mechanisms, which are implicated in a number of human diseases including deregulated cell proliferation in cancer and inflammatory responses in arthritis and asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059788-12
Application #
7907518
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
1999-08-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
12
Fiscal Year
2010
Total Cost
$285,912
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
Tatebe, Hisashi; Shimada, Koichi; Uzawa, Satoru et al. (2005) Wsh3/Tea4 is a novel cell-end factor essential for bipolar distribution of Tea1 and protects cell polarity under environmental stress in S. pombe. Curr Biol 15:1006-15

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