NGF (Nerve Growth Factor) regulates survival of several types of neurons by provoking a variety of signaling cascades including the PI 3-kinase/Akt pathway, which plays an essential role in this process. PI 3-kinase/Akt signaling blocks cell death by both impinging on the cytoplasmic apoptotic machinery and by mediating the expression of genes involved in cell death and survival. NGF elicits translocation of both PI 3-kinase and Akt to the nucleus, but little is known about the mechanisms of nuclear PI 3-kinase and Akt regulation. Elucidation of their mechanisms of action in the cell death machinery in neurons not only leads to a better understanding of nervous system development but also promises to provide multiple points of therapeutic intervention for neurodegenerative diseases. We have previously demonstrated that NGF treatment activates PIKE (PI 3-kinase Enhancer), a brain specific nuclear GTPase, which subsequently mediates activation of the nuclear PI 3-kinase. We have also shown that NGF triggers the translocation of PLC-Y1 to the nucleus, where it binds to PIKE and acts as a GEF (Guanine nucleotide Exchange Factor) for PIKE through its SH3 domain. However, the mechanism of PIKE GTPase regulation by GAP (GTPase Activating Protein) remains obscure. Recently, we found that PIKE binds to Akt and enhances its kinase activity, but the mechanisms by which PIKE interacts and stimulates Akt enzymatic activity remain elusive. Moreover, the biological consequences of this interaction are unclear. As a part of our long-term goal to understand NGF signaling cascades in neuronal differentiation, plasticity and cell survival, in this application we propose: 1) To determine the mechanism by which GAP mediates PIKE GTPase activity; 2) To define the interaction between PIKE and Akt and the effects of PIKE on Akt kinase activity; 3) To define the anti-apoptotic effects of PIKE/Akt interaction in NGF signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS045627-01A1
Application #
6731825
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Mamounas, Laura
Project Start
2004-01-01
Project End
2008-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
1
Fiscal Year
2004
Total Cost
$281,663
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Liu, Chaoyang; Chan, Chi Bun; Ye, Keqiang (2016) 7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders. Transl Neurodegener 5:2
Zhang, Zhentao; Xie, Manling; Ye, Keqiang (2016) Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases. Expert Opin Ther Targets 20:1237-45
Zhang, Zhentao; Song, Mingke; Liu, Xia et al. (2015) Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer's disease. Nat Commun 6:8762
Zhang, Zhentao; Song, Mingke; Liu, Xia et al. (2014) Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease. Nat Med 20:1254-62
Zhang, Zhentao; Liu, Xia; Schroeder, Jason P et al. (2014) 7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology 39:638-50
Chan, Chi Bun; Liu, Xia; Zhao, Lixia et al. (2014) PIKE is essential for oligodendroglia development and CNS myelination. Proc Natl Acad Sci U S A 111:1993-8
Liu, Xia; Obianyo, Obiamaka; Chan, Chi Bun et al. (2014) Biochemical and biophysical investigation of the brain-derived neurotrophic factor mimetic 7,8-dihydroxyflavone in the binding and activation of the TrkB receptor. J Biol Chem 289:27571-84
Tse, Margaret Chui Ling; Liu, Xia; Yang, Seran et al. (2013) Fyn regulates adipogenesis by promoting PIKE-A/STAT5a interaction. Mol Cell Biol 33:1797-808
Chan, Chi Bun; Chen, Yongjun; Liu, Xia et al. (2012) Essential role of PIKE GTPases in neuronal protection against excitotoxic insults. Adv Biol Regul 52:66-76
Sompol, Pradoldej; Liu, Xia; Baba, Kenkichi et al. (2011) N-acetylserotonin promotes hippocampal neuroprogenitor cell proliferation in sleep-deprived mice. Proc Natl Acad Sci U S A 108:8844-9

Showing the most recent 10 out of 47 publications