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.
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.
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