Coxsackie and adenovirus receptor (CAR): a multifunctional cell adhesion molecule

柯萨奇和腺病毒受体（CAR）：多功能细胞粘附分子

• 批准号: RGPIN-2017-05782
• 负责人: Nalbantoglu, Josephine
• 金额: $ 2.04万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=682195
• 关键词: Coxsackie; adenovirus; receptor; CAR; multifunctional

***The Coxsackie and adenovirus receptor (CAR) is a member of the immunoglobulin superfamily of adhesion molecules. As its name implies, it was first identified as the high affinity receptor for adenovirus type 5, the most commonly used adenoviral vector for gene transfer. My laboratory's interest in CAR stems from the fact that we routinely use adenovirus (Ad) vectors for gene transfer to muscle, nervous system and tumour cells. As such we have been interested in determining the expression pattern of CAR and means of modulating its expression. In the process, we have started studying the multiple functions of CAR in these tissues.***CAR expression is regulated developmentally and in a tissue-specific manner. Ectopic over expression studies in vitro indicate that the extracellular domain of CAR can mediate homotypic cell-cell adhesion. Accordingly CAR is localized to tight and adherens junctions in polarized epithelia. Highest levels of CAR expression are observed in prenatal and neonatal tissues. This pattern of expression suggests CAR could play a role in the growth, migration or differentiation of embryonic or neonatal tissues. Such a role for CAR is further supported by the observation of loss of CAR expression in several types of cancer. We were the first to show that the highly conserved cytoplasmic domain of CAR was essential for regulating cell migration. Through pulldown assays and proteomic analysis we have identified several binding partners, among which were the cytoskeletal proteins tubulin and actin, binding directly to CAR. We have also shown that CAR is processed by metalloproteases, specifically ADAM10, leading to shedding of its extracellular domain. This is followed by cleavage through the gamma-secretase complex to produce an intracellular cytoplasmic fragment, thus generating potentially important signalling molecules.***Our long term objective is to understand how an adhesion molecule such as CAR transmits extracellular cues into intracellular signals. In the past few years we have concentrated on two biological systems, tumour cells and neurons. In both cell types, CAR plays crucial roles in cell migration. In tumour cells, CAR expression leads to inhibition of migration and invasion while in neurons, CAR expression promotes process extension (neurite outgrowth).***Our specific aims are to:***1) determine the functional relevance of the processing of CAR***2) determine whether CAR's intracellular cytoplasmic domain plays a signaling role***3) study the function of CAR in the developing nervous system**

*** Coxsackie和腺病毒受体（CAR）是粘附分子的免疫球蛋白超家族的成员。顾名思义，它首先被鉴定为腺病毒5型腺病毒的高亲和力受体，这是最常用的基因转移腺病毒载体。我实验室对汽车的兴趣源于我们通常使用腺病毒（AD）向量将基因转移到肌肉，神经系统和肿瘤细胞的事实。因此，我们有兴趣确定汽车的表达模式和调节其表达的手段。在此过程中，我们已经开始研究这些组织中CAR的多个功能。*** CAR表达受到发育和组织特异性的调节。异位在体外表达研究表明，CAR的细胞外结构域可以介导同型细胞 - 细胞粘附。因此，汽车位于偏光性上皮的紧密连接处。在产前和新生儿组织中观察到最高水平的汽车表达。这种表达方式表明，汽车可以在胚胎或新生组织的生长，迁移或分化中发挥作用。在几种类型的癌症中观察到汽车表达丧失的进一步支持，这对汽车的作用得到了进一步的支持。我们是第一个表明汽车的高度保守的细胞质结构域对于调节细胞迁移至关重要。通过下拉分析和蛋白质组学分析，我们确定了几个结合伴侣，其中包括细胞骨架蛋白微管蛋白和肌动蛋白，直接与CAR结合。我们还表明，汽车是通过金属蛋白酶（特别是ADAM10）处理的，导致其细胞外域的脱落。接下来是通过γ-分泌酶复合物进行切割，以产生细胞内细胞质片段，从而产生潜在的重要信号分子。在过去的几年中，我们集中在两个生物系统，肿瘤细胞和神经元上。在两种细胞类型中，汽车在细胞迁移中扮演至关重要的作用。在肿瘤细胞中，CAR表达会导致抑制迁移和侵袭，而在神经元中，CAR表达促进过程延伸（神经突生长）。***我们的具体目的是：*** 1）确定CAR处理的功能相关性*** 2）CAR的功能相关性