Regulation and Function of hVps34 in Insulin Signaling

Project: Research project

Project Details

Description

Diabetes is a major public health problem in the United States and the world, with a huge societal cost in
both human and financial terms. Phosphoinositide 3-kinases (PI 3-kinases) are lipid kinases that play an
essential role in insulin action. While the function of p85/p110 PI 3-kinases in insulin responsive cells is well
documented, the Class III PI 3-kinase, hVps34, also plays an significant role in insulin action. In this
application, exciting new evidence is presented that links hVps34 to two nutrient sensing systems in
mammalian cells: the AMP-activated Protein Kinase (AMPK), which regulates the utilization of alternative
energy sources under low-nutrient conditions, and p70 S6-kinase (S6K), an key regulator of insulin-
stimulated protein synthesis. Data presented in this application show that overexpression of hVps34
activates S6K, and that inhibition of hVps34 blocks insulin stimulation of S6K. In addition, hVps34 is inhibited
by either glucose or amino acid starvation, conditions that also inhibit S6K. Finally, it is shown that hVps34 is
inhibited by activation of AMPK. These novel data suggest that hVps34 plays an important role in nutrient
sensing in mammalian cells;this is explored in four specific aims. Aim 1 examines the regulation of hVps34
by amino acids and glucose starvation, and will identify changes in hVps34 phosphorylation (using mass
spectrometry-based methods) and in hVps34-associated proteins that occurs in starved cells. Aim 2 studies
the role of AMPK in the inhibition of hVps34 in glucose-starved cells, and the mechanism of hVps34
regulation by AMPK. Aim 3 explores potential mechanisms of hVps34 signaling to S6K, including interactions
with mTOR, Cdc42, and CISK. Finally, Aim 4 examines the function of the hVps34-associated protein beclin-
1. These studies explore the mechanism of beclin-1-hVps34 association, and the role of beclin-1 in hVps34-
dependent vesicular trafficking and activation of S6K. Overall, these studies will have important implications
for our understanding of the function and regulation of hVps34, and its role in insulin action and diabetes.
StatusFinished
Effective start/end date3/6/062/28/11

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $305,655.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $291,441.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $291,441.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $297,389.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $21,818.00

ASJC

  • Genetics
  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.