A NOVEL REGULATORY MECHANISM OF A HUMAN LYMPHOCYTE METALLOPROTEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 ADAMS(去整合素和金属蛋白水解酶)是一种多结构域蛋白质，参与多种生物学事件，如受精、神经发生和免疫反应，以及肿瘤发生/发展、慢性炎症和阿尔茨海默病等疾病状态。在不同的哺乳动物物种中已鉴定出33个Adams，其中只有三分之一拥有表明功能金属蛋白水解酶的共有位点。尽管大多数已确定的ADAM成员缺乏蛋白分解活性，但这些不活跃的ADAM的生物学作用尚不清楚。活性ADAM金属蛋白水解酶是一类广泛存在的胞外结构域脱落酶，通过对细胞表面的生物活性因子(如细胞因子和生长因子)的专一性处理/切割来调节细胞外信号。活跃和非活跃的ADAM成员都能够通过其去整合素结构域介导整合素依赖的细胞黏附。蛋白水解性和粘附性之间的相互依赖关系在很大程度上仍未确定。基于目前非蛋白水解性ADAM结构域控制蛋白酶特异性的模型，该建议旨在描述非活性ADAMS在影响ADAM介导的脱落中所起的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ADAMs (a disintegrin and metalloprotease) are multidomain proteins that participate in a wide array of biological events such as fertilization, neurogenesis, and immune response as well as disease states such as tumor onset/progression, chronic inflammation, and Alzheimer's. The two defining domain structures, a disintegrin and metalloprotease, have established ADAMs as a novel class of proteins possessing both adhesive and proteolytic properties. Thirty-three ADAMs have been identified in various mammalian species with only one third possessing a consensus site indicative of a functional metalloprotease. Even though the majority of identified ADAM members lack proteolytic activity, the biological role of these inactive ADAMs is poorly defined. Active ADAM metalloproteases are well-characterized ectodomain sheddases capable of regulating extracelluar signals by obligate processing/cleavage of bioactive factors (e.g. cytokines and growth factors) from the cell surface. Both active and inactive ADAM members are capable of mediating integrin-dependent cell adhesion through their disintegrin domains. The interdependence of the proteolytic and adhesive specificities remains largely undefined. Based upon current models that nonproteolytic ADAM domains govern protease specificity, this proposal aims to delineate the role of inactive ADAMs in influencing ADAM-mediated shedding.