Coxsackie and adenovirus receptor (CAR): functions of a novel adhesion molecule

柯萨奇和腺病毒受体(CAR)是免疫球蛋白超家族黏附分子中的一个新成员。顾名思义，它首先被鉴定为对腺病毒5型的高亲和力受体，5型腺病毒是最常用的基因转移的腺病毒载体。我的实验室对CAR的兴趣源于我们常规使用腺病毒(Ad)载体将基因转移到肌肉、神经系统和肿瘤细胞。因此，我们一直有兴趣确定CAR的表达模式和调控其表达的方法，以及检测其在这些组织中的功能。 CAR的表达在发育过程中以组织特异性的方式受到调控。CAR在产前和新生儿组织中的表达水平最高。这种表达模式表明，CAR可能在胚胎或新生儿组织的生长、迁移或分化中发挥作用。CAR在几种类型的癌症中的表达缺失的观察进一步支持了CAR的这种作用。 我们的长期目标是了解像CAR这样的黏附分子是如何将细胞外信号转化为细胞内信号的。我们主要关注两个生物系统，肿瘤细胞和神经元。在这两种类型的细胞中，CAR在细胞迁移中起着至关重要的作用。在肿瘤细胞中，CAR的表达导致迁移和侵袭的抑制，而在神经元中，CAR的表达促进突起的延伸(突起生长)。我们已经证明，CAR可以经历金属蛋白酶介导的胞外结构域的脱落，然后通过伽马分泌酶复合体切割产生胞内片段，从而产生潜在的重要信号分子。在发育中的神经系统中，CAR的表达最高，这使得原代神经元培养和小鼠胚胎神经系统发育成为研究CAR功能的理想实验模型。我们的具体目标是：1)确定CAR的蛋白分解过程的功能相关性；2)确定CAR的胞浆结构域是否发挥信号作用；3)研究CAR在神经系统发育中的功能。

The Coxsackie and adenovirus receptor (CAR) is a novel 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 our routine use adenovirus (Ad) vectors for gene transfer to muscle, nervous system and tumour cells. Thus, we have been interested in determining the expression pattern of CAR and means of modulating its expression, as well as examining its function in these tissues. CAR expression is regulated developmentally and in a tissue-specific manner. 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. Our long term objective is to understand how an adhesion molecule such as CAR transmits extracellular cues into intracellular signals. 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). We have shown CAR can undergo metalloprotease-mediated shedding of its extracellular domain, followed by cleavage through the gamma-secretase complex to produce an intracellular cytoplasmic fragment, thus generating potentially important signalling molecules. CAR expression is highest in the developing nervous system, making primary neuronal cultures and mouse embryonic nervous system development the ideal experimental models to study CAR function. Our specific objectives are to:1) determine the functional relevance of the proteolytic 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.