Regulation of cell metabolism by LAR Phosphatase

白细胞共同抗原相关蛋白(LAR；又称PTPRF)是一种广泛表达的膜结合蛋白酪氨酸磷酸酶。LAR由一个含有多个免疫球蛋白和纤维连接蛋白III型粘附域的胞外区、一个跨膜区和两个胞内磷酸酶结构域组成。以前在细胞系和LAR基因敲除小鼠中的工作已经揭示了LAR在轴突引导、糖尿病、神经元退化和乳腺异常发育中的潜在作用。最近，我们使用了一种基于SILAC的蛋白质组学方法来分析小鼠胚胎成纤维细胞(MEF)中的信号转导，以及表达一种形式的LAR的MEF中缺乏两个细胞内磷酸酶结构域(LARP)。使用这种方法，我们已经确定了在缺乏LAR磷酸酶活性的细胞中蛋白质组的显着变化。对LARP细胞中显著上调或下调的蛋白质的GO术语分析显示，参与细胞新陈代谢的蛋白质显著丰富。该项目的目的是研究LAR调节这些代谢蛋白丰度的机制，并通过检测不同的代谢信号通路来研究这种调节的生物学后果。

Leucocyte common antigen-related protein (LAR; also known as PTPRF) is a widely expressed membrane bound protein tyrosine phosphatase. LAR is comprised of an extracellular region containing multiple immunoglobulin and fibronectin type III adhesion domains, a single transmembrane domain, and two intracellular phosphatase domains. Previous work in cell lines and in LAR-knockout mice has revealed potential roles for LAR in axon guidance, diabetes, neuron degeneration, and abnormal development of mammary glands. Recently, we have used a SILAC-based proteomics approach to analyse signalling in mouse embryo fibroblasts (MEFs) and in MEFs expressing a form of LAR lacking the two intracellular phosphatase domains (LARP). Using this approach we have identified significant changes to the proteome in cells lacking LAR phosphatase activity. GO Term analysis of proteins significantly up- or down-regulated in LARP cells revealed a striking enrichment of proteins involved in cell metabolism. The aims of this project are to investigate the mechanism by which LAR regulates the abundance of these metabolic proteins, and to examine the biological consequences of this regulation by examining distinct metabolic signalling pathways.