Novel Regulation of Receptor Tyrosine Kinases by ASM (Acidic Sphingomyelinase)

项目摘要 我们认为ASM(酸性鞘氨酸肌氨酸酶)是RTK(受体酪氨酸激酶)的关键调节因子，并且 ASM可作为治疗多种癌症的新靶点，包括多形性胶质母细胞瘤。 (GBM)。此外，由于ASM功能的丧失可能导致罕见的 家族性Niemann Pick病，A型，我们的研究可能提供对该疾病的分子洞察。 质膜是主要由磷脂和鞘磷脂组成的脂双层， 胆固醇、鞘糖脂和其他含量较低的脂质分子，如礼仪。的组成 质膜脂是动态调节的，并与细胞内快速交换。 通过分泌、胞吞和内吞等细胞器，如高尔基体、内小体和溶酶体。对许多人来说 跨膜和膜相关蛋白，包括RTKs，与各种脂质的特异性相互作用 质膜中的分子是调节的组成部分，以维持其蛋白质结构和 功能。然而，特定的脂质分子调节RTK动态活性的机制 而其他跨膜或膜相关蛋白的特性还不是很好。在此应用程序中，我们 建议研究ASM(也称为SMPD1)在调节RTK介导的细胞信号转导中的作用 流程。 我们最近发现，在GBM和OUR中，ASM(酸性鞘磷脂酶)水平高度升高。 研究表明，ASM是激活多个RTK所必需的。ASM是一种参与 神经鞘磷脂代谢能将神经鞘磷脂水解物产生神经酰胺。神经酰胺，与生物物理 自缔合的性质，与建立促进蛋白质-蛋白质的脂质微环境有关 互动。人类ASM基因突变导致Niemman-Pick病，A型，一种遗传性疾病 会导致小脑浦肯野神经元的大量丧失，患者通常会在2或3岁时死亡，但 ASM缺乏对该病的潜在分子机制仍未解决。 在这个应用中，我们将研究ASM调节RTK信号通路的机制，通过 以下是具体目标： 具体目的1：确定ASM如何调节激活的RTK受体蛋白。 特异性目的2：探讨ASM鞘磷脂酶活性在RTK信号转导中的作用。 具体目的3：研究ASM是否在多个水平上调节RTK信号。 由于RTK的共激活在GBM和许多人类疾病和疾病中至关重要， 阐明这一新的调控机制可能为预防和治疗提供新的靶点 治疗。我们的研究也应该提供ASM功能丧失如何导致神经元的分子基础 人类疾病的退化，如Niemman-Pick病，A型。

Project Summary We propose that ASM (acid sphingomylinase) is a critical regulator of RTKs (receptor tyrosine kinases), and that ASM can serve as a novel therapeutic target for various cancers, including gliomablastoma multiforme (GBM). Also as loss of function of ASM may cause the severe neuron degeneration phenotype in the rare familial Niemann Pick Disease, type A, our studies may provide molecular insights into this disease. The plasma membrane is a lipid bilayer composed primarily of phospholipids, as well as sphingomyelins, cholesterol, glycosphingolipids and other less abundant lipid molecules such as ceremides. The composition of the plasma membrane lipids is dynamically regulated and undergoes rapid exchanges with intracellular organelles such as Golgi, endosomes and lysosomes through secretion, exocytosis and endocytosis. For many transmembrane and membrane-associated proteins, including RTKs, specific interaction with various lipid molecules in the plasma membrane is an integral part of regulation to maintain their protein structure and function. However, the mechanisms by which specific lipid molecules regulate the dynamic activities of RTKs and other transmembrane or membrane-associated proteins are not well characterized. In this application, we propose to investigate the roles of ASM (also called SMPD1) in regulating the RTK-mediated cell signaling processes. We have recently found that the levels of ASM (acidic sphinomyelinase) are highly elevated in GBM and our studies reveal that ASM is required for the activation of multiple RTKs. ASM is an enzyme involved in sphingolipid metabolism that hydrolyzes sphingomyelin to produce ceramide. Ceramide, with a biophysical property of self-association, is involved in establishing a lipid microenvironment that promotes protein-protein interactions. Mutations of human ASM gene cause Niemman-Pick disease, type A, an inherited disease that induces massive loss of Purkinje neurons in the cerebellum and patients usually die by 2 or 3 years of ages, but the underlying molecular mechanism of ASM deficiency for the disease remains unresolved. In this application, we will investigate the mechanism by which ASM regulates the RTK signaling pathway, by following specific aims: Specific aim 1: To determine how ASM regulates the activation RTK receptor proteins. Specific aim 2: To investigate the involvement of ASM sphinomyelinase activity in RTK signaling. Specific aim 3: To examine whether ASM regulates RTK signaling at multiple levels. As co-activation of RTKs is critically important in GBM and in a multitude of human disorders and diseases, elucidation of this new regulatory mechanism may provide novel targets for prevention and therapeutic treatment. Our studies should also provide molecular underpinning how loss-of-function of ASM causes neuron degeneration in the human diseases such as Niemman-Pick disease, type A.