Nuclear GTPase PIKE regulation and functions

摘要 Pike(PI 3-Kinase Enhancer)是一种脑特异性GTP酶，可增强PI 3-K(PI3K)活性。派克捆绑 并以GTP依赖的方式刺激PI3K活性。PLC-G1作为鸟嘌呤激活派克 核苷酸交换因子。在海马神经元中，激活I组代谢性谷氨酸 受体(MGluRI)刺激mGluRI-荷马-派克-L复合体的形成，导致PI3K的激活 和防止神经细胞凋亡。我们的初步研究表明，netrin-1诱导了 Unc5b，一种Netrin受体，与Pike-L一起触发PI3K信号的激活，并阻止Unc5b 促进细胞凋亡的活性，提高神经元的存活率。Pike和Unc5b之间的关联是中介的 通过Netrin激活的Fyn酪氨酸激酶。与这一观察结果一致的是，Pike缺陷小鼠很容易受到攻击。 神经兴奋性毒性或中风引起的神经细胞凋亡。此外，我们发现Akt反馈和 磷酸化派克-L。然而，这一事件的生物学意义仍然难以捉摸。我们假设 Pike在NGF诱导的神经元存活、netrin介导的神经元存活和netrin受体中起关键作用 二聚化。这项拟议研究的目的是确定GTP酶的生理功能 PIKE(PI 3-Kinase Enhator)在多种细胞过程中的作用，包括NGF介导的神经元存活和 使用Pike基因敲除小鼠的netrin-1信号。派克对分子机制的表征 神经元中的细胞死亡机制不仅有助于更好地了解神经系统的发育，而且 还承诺为神经退行性疾病提供多点治疗干预。

Abstract 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.