Cell growth-dependent control of secretion by lipid signals

描述(由申请人提供)：生长对所有生物体的细胞增殖和分化都是必不可少的，如果调控不当，会导致一系列严重的人类疾病。细胞表面的生长很大程度上依赖于通过分泌途径将膜和蛋白质协调输送到细胞外周。虽然这一现象已经被认识到几十年了，但生物合成途径是如何响应生长信号的还不清楚。最近，磷酸化的脂类被认为与调节细胞生长的特定过程有关。基于我们的初步证据，我们提出了肌醇磷脂在分泌物生长调节中的核心作用。虽然已经确定肌醇磷脂对细胞内膜运输是必不可少的，但生物合成途径中的脂质信号与细胞生长之间的联系尚未被表征。在这项提案中，我们的目的是证明SAC1脂磷酸酶在细胞生长过程中调节分泌途径中的一个新的和重要的角色。我们的初步研究表明，人类SAC1在内质网(ER)和高尔基体之间穿梭，对生长条件做出反应，并调节这些细胞器的脂质信号。我们的目标是阐明SAC1依赖生长的穿梭机制，并分析SAC1在分泌和细胞增殖中的作用。我们将从三个不同的目标来调查这些问题。具体地说，我们将描述SAC1在内质网和高尔基体之间易位的生长调节机制。我们将分析SAC1如何在内质网和高尔基体调节肌醇磷脂，以及这种调节如何与细胞器功能和贩运有关。最后，我们将确定控制SAC1定位的有丝分裂原依赖的信号通路，并研究这一过程与静止细胞的生长刺激和肿瘤细胞生长的关系。表征分泌和细胞生长的分子机制将有助于识别新的药物靶点，并最终有助于预防由细胞异常增殖引起的疾病。公共卫生相关性：肌醇磷脂信号的缺陷会导致人类疾病，包括癌症、糖尿病和肾脏疾病。表征基于磷脂酰肌醇的调节，整合分泌和细胞生长，将有助于确定预防或治愈此类疾病的新药物靶点。

DESCRIPTION (provided by applicant): Growth is essential for cell proliferation and differentiation in all organisms and causes a wide range of severe human diseases if misregulated. Cell surface growth relies critically on coordinated delivery of membranes and proteins to the cell periphery via the secretory pathway. Although this phenomenon has been recognized for several decades, it remains unknown how the biosynthetic pathway is regulated in response to growth signaling. Phosphorylated lipids have been recently implicated in regulating cell growth-specific processes. Based on our preliminary evidence, we propose a central role for phosphoinositide lipids in growth regulation of secretion. While it is established that phosphoinositides are essential for intracellular membrane traffic, a link between lipid signaling within the biosynthetic pathway and cell growth has not been characterized. In this proposal, we aim to demonstrate a novel and essential role for the SAC1 lipid phosphatase in the regulation of the secretory pathway during cell growth. Our preliminary studies show that human SAC1 shuttles between endoplasmic reticulum (ER) and Golgi in response to growth conditions and regulates lipid signaling at these organelles. Our goal is to elucidate the mechanism of growth-dependent shuttling of SAC1 and to analyze the role of SAC1 in secretion and cell proliferation. We will investigate these questions in three distinct aims. Specifically, we will characterize the growth-regulated mechanism of SAC1 translocation between ER and Golgi. We will analyze how SAC1 regulates phosphoinositides at ER and Golgi and how this regulation relates to organellar function and trafficking. Finally we will identify the mitogen-dependent signaling pathway that controls SAC1 localization and we will examine how this process is related to growth stimulation of quiescent cells and to tumor cell growth. Characterization of the molecular mechanisms that integrate secretion and cell growth will lead to the identification of novel classes of drugs targets and eventually help preventing diseases stemming from abnormal cell proliferation. PUBLIC HEALTH RELEVANCE: Defects in phosphoinositide signaling cause human disease including cancer, diabetes and kidney disease. Characterization of the phosphoinositide-based regulation that integrates secretion and cell growth will facilitate identification of novel drug targets to prevent or cure such diseases.