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至关重要，如果调节不当，会导致多种严重的人类疾病。细胞表面生长主要依赖于膜和蛋白质通过分泌途径向细胞周围的协调传递。尽管这一现象在几十年前就已经被认识到，但生物合成途径是如何响应生长信号而被调节的仍是未知的。磷酸化脂质最近被认为与调节细胞生长特异性过程有关。基于我们的初步证据，我们提出磷肌醇脂在生长调节分泌中的核心作用。虽然已经确定磷酸肌苷对细胞膜内运输至关重要，但生物合成途径中的脂质信号传导与细胞生长之间的联系尚未被表征。在这个提议中，我们的目标是证明SAC1脂质磷酸酶在细胞生长过程中调节分泌途径的一个新的和重要的作用。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，以响应生长条件并调节这些细胞器的脂质信号。我们的目标是阐明SAC1的生长依赖性穿梭机制，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研究这些问题。具体来说，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如何调节内质网和高尔基体的磷酸肌苷，以及这种调节如何与细胞器功能和运输相关。最后，我们将确定控制SAC1定位的丝裂原依赖性信号通路，并研究该过程如何与静止细胞的生长刺激和肿瘤细胞生长相关。对整合分泌和细胞生长的分子机制的表征将导致识别新型药物靶点，并最终帮助预防由异常细胞增殖引起的疾病。公共卫生相关性：磷酸肌苷信号缺陷导致人类疾病，包括癌症、糖尿病和肾脏疾病。对磷肌肽为基础的整合分泌和细胞生长的调控进行表征，将有助于识别新的药物靶点，以预防或治疗此类疾病。

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.