A NOVEL TYPE II TRANSMEMBRANE MATRIX METALLOPROTEINASE

描述：（改编自研究者摘要）长期目的 本研究的一个目的是鉴定一种新的金属蛋白酶CA-MMP （半胱氨酸阵列基质金属蛋白酶）/MMP 23，并确定其在 重塑细胞外基质（ECM）。由一群不同的 大分子如胶原蛋白和弹性蛋白，ECM充当分子胶 将细胞固定在一起，提供结构支架， 以及发育线索，以指定细胞在何时何地， 人体ECM的异常转换与疼痛和 致命的疾病，如癌症。恶性肿瘤细胞获得侵袭性和 转移表型部分通过调节表达强大的 蛋白水解酶，使他们能够破坏结构障碍， ECM。因此，人们对识别和表征 能够破坏ECM的蛋白水解酶。这种蛋白酶的一个家族， 称为基质降解金属蛋白酶（MMP），已涉及 ECM破坏是由于它们能够降解蛋白质， ECM组件。在本申请中，一种新的金属蛋白酶（CA-MMP/MMP 23） 被描述为仅与MMPs共享催化结构域，但与其自身的 不同的前和羧基结构域，因此代表了一个潜在的新的 MMP超家族的一个成员。值得注意的是，这个新基因包含一个II型 跨膜结构域，缺乏经典的半胱氨酸开关的潜伏期，并具有 在其C末端存在一个新型半胱氨酸阵列和免疫球蛋白样结构域。所以他们 假设CA-MMP合成并在细胞膜上展示为一种类型 II膜蛋白酶，在细胞膜中被弗林蛋白酶转化为可溶性和活性形式。 transGolgi网络，并被细胞用来降解蛋白质底物， 由其Cys-阵列（CA）结构域和免疫球蛋白折叠指定。测试 根据这一假设，将追求以下具体目标：1）建立 CA-MMP作为第一个具有II型跨膜锚的MMP，并表征 弗林蛋白酶作为其分泌酶，2）确定CA-MMP的潜伏机制，和3） 建立CA-MMP作为一种独特的蛋白水解酶，可以与新的 蛋白质伴侣通过其C-末端结构域。从这三个知识 方法将最终有助于我们理解CA-MMP， 病理生理过程涉及ECM重塑和增强我们的能力， 对抗与ECM相关的退行性疾病。

DESCRIPTION: (Adapted from the investigator's abstract) The long-term objective of this proposal is to characterize a novel metalloproteinase named CA-MMP (Cysteine-Array Matrix MetalloProteinase)/MMP23 and define its function in remodeling extracellular matrix (ECM). Composed of a diverse group of macromolecules such as collagens and elastins, ECM serves as molecular glue holding cells together to provide the structural scaffold for physical strength as well as developmental cues to specify where and when the cells are in the human body. Aberrant turnover of the ECM has been associated with painful and lethal diseases such as cancer. Malignant tumor cells acquire the invasive and metastatic phenotype in part by regulating the expression of powerful proteolytic enzymes that allow them to destroy the structural barriers made of ECM. Thus, there has been intense interest in identifying and characterizing proteolytic enzymes capable of destroying ECM. One family of such proteinases, known as the matrix-degrading metalloproteinases (MMP), has been implicated in ECM destruction by virtue of their ability to degrade the proteinaceous components of ECM. In this application, a new metalloproteinase (CA-MMP/MMP23) is described to share only the catalytic domain with MMPs, but with its own distinct pro- and carboxyl- domains, thus representing a potentially new subfamily of the MMP superfamily. Notably, this new gene contains a type II transmembrane domain, lacks a classic cysteine-switch for latency and possesses a novel cysteine-array and Ig-like domain at its C-terminus. Thus, they hypothesize that CA-MMP is synthesized and displayed on cell membrane as a type II membrane proteinase, converted into soluble and active form by furin in the transGolgi network, and utilized by cells to degrade protein substrates as specified by its Cys-array (CA) domain and the immunoglobulin fold. To test this hypothesis, the following specific aims will be pursued: 1) Establish CA-MMP as the first MMP with a type II transmembrane anchor and characterize furin as its secretase, 2) Define the latency mechanism of CA-MMP, and 3) Establish CA-MMP as a unique proteolytic enzyme which can interact with novel protein partners via its C-terminal domains. Knowledge from these three approaches will ultimately contribute to our understanding of CA-MMP in pathophysiological process involving ECM remodeling and enhance our ability to fight degenerative diseases associated with ECM.