SHIP PROTEINS AND SIGNAL TRANSDUCTION

船舶蛋白和信号转导

• 批准号: 2885530
• 负责人: Larry Ray Rohrschneider
• 金额: $ 29.7万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2885530
• 关键词: RNA splicing; biological signal transduction; carcinogenesis; cell biology; cell growth regulation; colony stimulating factor; enzyme activity; enzyme linked immunosorbent assay; gel electrophoresis; genetic mapping; genetically modified animals; growth factor receptors; hematopoiesis; immunoprecipitation; inositol phosphates; laboratory mouse; laboratory rabbit; nucleic acid sequence; polymerase chain reaction; protein binding; protein isoforms; protein protein interaction; protein signal sequence; protein structure function; western blottings; yeast two hybrid system

The M-CSF (macrophage colony stimulating factor) receptor, Fms, regulates the growth and development of the monocyte-macrophage lineage of blood cells. The structure of Fms is shared by several other tyrosine kinase growth factor receptors (e.g., the PDGF receptors, Kit, Flt3, and the FGF group of receptors) that transduce similar signals in distinct cells and tissues. In humans, mutations of some of these receptors result in disease states of the blood or tissues in which they are expressed, and our goal is to understand the diverse molecular mechanisms of signaling by this class of receptors using Fms as a paradigm. Recently we identified a new type of signal transduction protein designated SHIP for its structure (SH2-containing) and enzymatic function Inositol 5- Phosphatase activity). SHIP is expressed in most cells of the blood and tyrosine phosphorylated by multiple cytokines and their receptors, and surprisingly, exhibits negative growth regulation. Homologs of SHIP probably exist in most, if not all cells and tissues of eukaryotes. Therefore, SHIP has the potential to suppress or modulate positive growth factor receptor signaling and its relevance to the growth and differentiation signals regulated by Fms would be helpful to understand its role in normal growth and potential abnormalities in cancer. The focus of the proposed studies will be on biochemical studies of the signal transduction mechanism involving SHIP, production of transgenic and knockout mice for the investigation of the functional role of SHIP isoforms in individual blood cell lineages, and characterization of the genomic and spliced isoforms of SHIP to determine their role in normal blood cell development and contribution to leukemia development.

FMS的M-CSF（巨噬细胞刺激因子）受体调节血细胞单核细胞巨噬细胞谱系的生长和发育。 FMS的结构由其他几种酪氨酸激酶生长因子受体（例如，PDGF受体，试剂盒，FLT3和FGF受体组）共享，它们在不同的细胞和组织中转导相似的信号。在人类中，其中某些受体的突变导致表达其血液或组织的疾病状态，我们的目标是使用FMS使用FMS作为范式来理解该类别受体的信号传导的不同分子机制。最近，我们确定了一种新型的信号转导蛋白指定的船，用于其结构（含SH2）和酶促功能肌醇5-磷酸酶活性）。船在大多数由多种细胞因子及其受体磷酸化的血液和酪氨酸细胞中表达，令人惊讶地表现出阴性生长调节。船的同源物可能存在于真核生物的大多数（如果不是全部）中。因此，船有可能抑制或调节正生长因子受体信号及其与FMS调节的生长和分化信号的相关性将有助于了解其在正常生长中的作用和在癌症中的潜在异常。拟议的研究的重点将放在涉及船舶，转基因和基因敲除小鼠的信号转导机制的生化研究上，以研究造船同工型在单个血细胞谱系中的功能作用，以及对船舶基因组和跨性质的表征的表征，以确定其在正常血细胞发育中的作用，以确定其在正常血细胞发育中的作用。