PIKE (PI 3-kinase Enhancer) is a brain specific GTPase that enhances PI 3-kinase (PI3K) activity. PIKE binds and stimulates PI3K activity in a GTP-dependent manner. PLC-g1 activates PIKE by acting as a guanine nucleotide exchange factor (GEF). In hippocampal neurons, activation of group I metabotropic glutamate receptors (mGluRIs) stimulates formation of an mGluRI-Homer-PIKE-L complex, leading to activation of PI3K and prevention of neuronal apoptosis. Our preliminary studies show that netrin-1 induces interaction of UNC5B, a netrin receptor, with PIKE-L, which triggers activation of PI3K signaling, and prevents UNC5B's pro-apoptotic activity and enhances neuronal survival. The association between PIKE and UNC5B is mediated by netrin-activated Fyn tyrosine kinase. In alignment with this observation, PIKE deficient mice are vulnerable to neuroexcitotoxicity or stroke-provoked neuronal apoptosis. Moreover, we found that Akt feeds back and phosphorylates PIKE-L. However, the biological significance of this event remains elusive. We hypothesize that PIKE is critical for NGF-provoked neuronal survival, netrin-mediated neuronal survival and netrin receptor dimerization. The objective of this proposed research is to determine the physiological functions of GTPase PIKE (PI 3-Kinase Enhancer) in various cellular processes including NGF-mediated neuronal survival and netrin-1 signaling using PIKE knockout mice. Characterization of the molecular mechanisms by PIKE 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.

Public Health Relevance

Nuclear GTPase PIKE Regulation and Functions Project Narrative PIKE (PI 3-Kinase Enhancer) is critical for mediating cell survival through PI 3-kinase/Akt signaling pathway. NGF treatment activates PI 3-kinase partially through PIKE GTPase in primary neurons. Recently, we found that netrin-1 induces interaction of UNC5B, a netrin receptor, with PIKE-L, which triggers activation of PI3K signaling, and prevents UNC5B's pro-apoptotic activity and enhances neuronal survival. The association between UNC5B and PIKE-L is regulated by Fyn-mediated tyrosine phosphorylation on both UNC5B and PIKE-L. Moreover, PIKE deficient mice are vulnerable to neuroexcitotoxicity or stroke-provoked neuronal apoptosis. In addition, we found that Akt feeds back and phosphorylates PIKE. However, the biological significance of this event remains elusive. We hypothesize that PIKE is critical for NGF-provoked neuronal survival and netrin-mediated neuronal signalings. In the current proposal, we will examine these hypotheses. Successful accomplishment of the proposed projects not only leads to a better understanding of nervous system development but also promises to provide multiple points of therapeutic intervention for neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045627-10
Application #
8533008
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Mamounas, Laura
Project Start
2003-04-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$320,652
Indirect Cost
$113,780
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
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
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
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
Andero, Raul; Heldt, Scott A; Ye, Keqiang et al. (2011) Effect of 7,8-dihydroxyflavone, a small-molecule TrkB agonist, on emotional learning. Am J Psychiatry 168:163-72
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
He, Kunyan; Jang, Sung-Wuk; Joshi, Jayashree et al. (2011) Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner. Mol Biol Cell 22:1943-54
Chan, Chi Bun; Liu, Xia; Pradoldej, Sompol et al. (2011) Phosphoinositide 3-kinase enhancer regulates neuronal dendritogenesis and survival in neocortex. J Neurosci 31:8083-92
Jang, Sung-Wuk; Liu, Xia; Yepes, Manuel et al. (2010) A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci U S A 107:2687-92

Showing the most recent 10 out of 42 publications