Nuclear GTPase PIKE Regulation and Functions

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DESCRIPTION (provided by applicant): 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.