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

ASM（酸性鞘磷脂酶）对受体酪氨酸激酶的新调控

• 批准号: 9232921
• 负责人: HONG SUN
• 金额: $ 42.8万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2020-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232921
• 关键词: 3 year old; Ablation; Acids; Apoptosis; Bacterial Infections; Biochemical; Brain; Caenorhabditis elegans; Cancer Cell Growth; Cell Signaling Process; Cell Survival; Cell membrane; Cell surface; Cells; Ceramides; Cerebellum; Cessation of life; Cholesterol; Classical Niemann-Pick Disease; Complex; Deterioration; Disease; Docking; Drug resistance; Endocytosis; Endosomes; Enzymes; Exocytosis; Family; Genes; Genetic Models; Glycosphingolipids; Golgi Apparatus; Growth; Homologous Gene; Human; Hydrolysis; Image; Inherited; Insulin-Like-Growth Factor I Receptor; Integral Membrane Protein; Island; Lateral; Lead; Link; Lipid Bilayers; Lipids; Liver; Lung; Lysosomes; Malignant Neoplasms; Mammalian Cell; Mediating; Membrane; Membrane Lipids; Membrane Microdomains; Membrane Proteins; Metabolism; Molecular; Monitor; Movement; Mutation; Nerve Degeneration; Neurologic; Neurons; Niemann-Pick Diseases; Organelles; Pathway interactions; Patients; Phenotype; Phospholipids; Physiological; Pick Disease of the Brain; Prevention; Production; Protein Dynamics; Proteins; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Role; Sea; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Sphingolipids; Sphingomyelinase Deficiency Diseases; Sphingomyelins; Spleen; Stimulus; Stress; Structure; Surface; System; TNFRSF6 gene; Tail; Testing; Therapeutic; Time; Transmembrane Domain; Tyrosine; Ultraviolet Rays; acid sphingomyelinase; acidic sphingomyelinase; base; biophysical properties; cancer cell; early childhood; functional genomics; human disease; insight; live cell imaging; loss of function; loss of function mutation; meetings; mutant; neuron loss; new therapeutic target; novel; physical property; protein protein interaction; protein structure function; receptor; response; signal processing; src-Family Kinases

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.

项目摘要 我们认为ASM（酸性鞘磷脂酶）是RTK（受体酪氨酸激酶）的关键调节因子， ASM可以作为多种癌症新的治疗靶点，包括多形性胶质母细胞瘤 （GBM）。此外，由于ASM功能丧失可能导致罕见的神经元变性表型， 家族性尼曼匹克病，A型，我们的研究可能会提供这种疾病的分子见解。 质膜是主要由磷脂以及鞘磷脂组成的脂质双层， 胆固醇、鞘糖脂和其它不太丰富的脂质分子如蜡酰亚胺。的组合物 质膜脂质是动态调节的，并与细胞内的脂质进行快速交换， 细胞器如高尔基体、内体和溶酶体通过分泌、胞吐和胞吞作用。对于许多 跨膜和膜相关蛋白，包括RTK，与各种脂质的特异性相互作用 质膜中的分子是维持其蛋白质结构的调节的组成部分， 功能然而，特定脂质分子调节RTK动态活性的机制 而其它跨膜或膜相关蛋白没有得到很好的表征。在本申请中，我们 本文拟研究ASM（也称为SMPD 1）在调控RTK介导的细胞信号转导中的作用 流程. 我们最近发现，ASM（酸性鞘磷脂酶）的水平在GBM中高度升高， 研究表明，ASM是激活多种RTK所必需的。ASM是一种酶， 水解鞘磷脂产生神经酰胺的鞘脂代谢。神经酰胺，具有生物物理 自缔合的性质，参与建立脂质微环境，促进蛋白质-蛋白质 交互.人类ASM基因突变导致A型尼曼-皮克病，这是一种遗传性疾病， 引起小脑浦肯野神经元的大量损失，患者通常在2或3岁时死亡， ASM缺陷导致该疾病的潜在分子机制仍未解决。 在本申请中，我们将研究ASM调节RTK信号通路的机制， 具体目标如下： 具体目标1：确定ASM如何调节RTK受体蛋白的活化。 具体目标2：研究ASM鞘磷脂酶活性在RTK信号传导中的参与。 具体目标3：检查ASM是否在多个水平上调节RTK信号传导。 由于RTK的共激活在GBM和许多人类病症和疾病中至关重要， 阐明这种新的调节机制可能为预防和治疗提供新的靶点。 治疗我们的研究还应该提供ASM功能丧失如何导致神经元损伤的分子基础。 在人类疾病如A型尼曼-皮克病中的变性。