Most organisms have evolved numerous regulatory mechanisms for sensing glucose and utilizing it efficiently. Glucose sensing and signaling in yeast remains an important paradigm for understanding molecular mechanisms that link extracellular signals to changes in an organism's transcriptional program. The budding yeast Saccharomyces cerevisiae has a distinctive fermentative life style?the preferential conversion of glucose into ethanol even under aerobic conditions?that it shares with many different tumor cells. This specialized glucose metabolism is accomplished by coordinated actions of two distinct glucose-regulated pathways: 1) the Rgt2/Snf3 glucose induction pathway that induces expression of glucose transporter genes (HXT);2) the Snf1-Mig1 glucose repression pathway that negatively regulates genes involved in respiration and the use of alternative sugars. The goal of the proposed research is to understand the role of glucose sensors in establishing not only the glucose induction but also the glucose repression of gene expression.
In Aim 1, we will examine the mechanism by which glucose induction of HXT expression is achieved by the crosstalk between different glucose signaling pathways.
In Aim 2, we will address the question of how the glucose sensors recognize and sense different levels of glucose. The glucose sensors are structurally similar to the glucose transporters but lack the ability to transport glucose. Achieving this aim would provide significant insights into the mechanism of glucose transport. Recent evidences suggest that Hxk2, one of the three hexose kinases, establishes an independent glucose repression pathway which is distinctive from the Snf1-Mig1 glucose repression pathway. The goal of aim 3 is to understand the Hxk2-mediated glucose signaling mechanism.
In Aim 4, we will explore the multiple roles of the glucose sensors in glucose repression. We will specifically identify the regulatory role of the glucose sensors in inactivating the function of the Snf1 kinase, a yeast homolog of the AMP-activated protein kinase (AMPK), known to have direct links to diabetes and obesity.

Public Health Relevance

The primary goal of the proposed research is to understand the complex crosstalk between the glucose signaling pathways in yeast. The proposed studies will provide significant insights into the processes involved in the maintenance of glucose homeostasis in humans, especially under pathological conditions, such as hyperglycemia in diabetics and the elevated rate of glycolysis observed in many solid tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM087470-04
Application #
8288165
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
2009-09-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$227,011
Indirect Cost
$81,956
Name
George Washington University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
Roy, Adhiraj; Kim, Jeong-Ho (2014) Endocytosis and vacuolar degradation of the yeast cell surface glucose sensors Rgt2 and Snf3. J Biol Chem 289:7247-56
Roy, Adhiraj; Kim, Yong-Bae; Cho, Kyu Hong et al. (2014) Glucose starvation-induced turnover of the yeast glucose transporter Hxt1. Biochim Biophys Acta 1840:2878-85
Roy, Adhiraj; Jouandot 2nd, David; Cho, Kyu Hong et al. (2014) Understanding the mechanism of glucose-induced relief of Rgt1-mediated repression in yeast. FEBS Open Bio 4:105-11
Shin, Yong Jae; Kim, Yong-Bae; Kim, Jeong-Ho (2013) Protein kinase CK2 phosphorylates and activates p21-activated kinase 1. Mol Biol Cell 24:2990-9
Roy, Adhiraj; Shin, Yong Jae; Cho, Kyu Hong et al. (2013) Mth1 regulates the interaction between the Rgt1 repressor and the Ssn6-Tup1 corepressor complex by modulating PKA-dependent phosphorylation of Rgt1. Mol Biol Cell 24:1493-503
Roy, Adhiraj; Shin, Yong Jae; Kim, Jeong-Ho (2013) Construction of yeast strains useful for screening drugs that inhibit glucose uptake and glycolysis. Anal Biochem 436:53-4
Tesorero, Rafael A; Yu, Ning; Wright, Jordan O et al. (2013) Novel regulatory small RNAs in Streptococcus pyogenes. PLoS One 8:e64021
Kim, Jeong-Ho; Roy, Adhiraj; Jouandot 2nd, David et al. (2013) The glucose signaling network in yeast. Biochim Biophys Acta 1830:5204-10
Shin, Yong Jae; Kim, Eun Hye; Roy, Adhiraj et al. (2013) Evidence for a novel mechanism of the PAK1 interaction with the Rho-GTPases Cdc42 and Rac. PLoS One 8:e71495
Shin, Yong Jae; Kim, Jeong-Ho (2012) The role of EZH2 in the regulation of the activity of matrix metalloproteinases in prostate cancer cells. PLoS One 7:e30393

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