FUNCTION OF THE MEMBRANE TYPE MATRIX METALLOPROTEINASE

膜型基质金属蛋白酶的功能

• 批准号: 2683667
• 负责人: STEPHEN J WEISS
• 金额: $ 26.05万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-11 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2683667
• 关键词: collagenase; enzyme activity; enzyme biosynthesis; enzyme substrate; extracellular matrix; membrane proteins; metalloendopeptidases; pepsin; polymerase chain reaction; tissue /cell culture; zymogens

DESCRIPTION: Cancer cells invade surrounding tissues and metastasize by controlling the expression of proteolytic enzymes that allow them to degrade the structural barriers established by the extracellular matrix. One group of proteinases, known as the matrix-degrading metalloproteinases or MMPs, is currently believed to play a prominent role in cancer progression since these enzymes can, in concert, degrade all of the major proteinaceous components of the extracellular matrix including collagens, elastin and proteoglycans. Recently, the first membrane-anchored member of the MMP family, termed the membrane-type MMP (MT-MMP), was identified and shown to be expressed at heightened levels in a variety of human carcinomas. Based on the ability of MT-MMP to activate progelatinase A (an additional member of the MMP family with broad spectrum, matrix-degrading activity), it has been postulated that this new metalloproteinase may act as the master switch that regulates the expression of the tissue-invasive phenotype in cancer cells. However, like all members of the MMP family, MT-MMP itself is synthesized as a zymogen that must be processed to its active form in order to express catalytic activity. Presently, the factors regulating MT-MMP activation are unknown as are the molecular characteristics of the MT-MMP progelatinase A interaction. Furthermore, technical complexities associated with the purification of transmembrane enzymes have precluded efforts to determine whether active MT-MMP (or its active derivatives) expresses additional proteolytic activities that affect or regulate the tissue-invasive properties of cancer cells. To address these issues, the applicant proposes to use a series of molecular, biochemical and cellular approaches to I) characterize the regulatory processes that control the processing of the MT-MMP zymogen to its active form, ii) define the molecular basis of MT-MMP-dependent progelatinase A activation, iii) characterize the enzymic properties of membrane-anchored and soluble forms of MT-MMP and iv) assess the ability of MT-MMP to regulate the behavior of cancer cells in an in vivo-like model of the extracellular matrix. These studies should not only provide new insights into the role of MT-MMP in cancer progression, but also its potential importance as a target for novel therapeutic interventions.

描述：癌细胞侵入周围组织并通过以下方式转移： 控制蛋白水解酶的表达， 由细胞外基质建立的结构屏障。 一组 称为基质降解金属蛋白酶或MMPs的蛋白酶， 目前认为在癌症进展中起着重要作用， 这些酶可以协同降解所有主要的蛋白质， 细胞外基质的成分，包括胶原蛋白、弹性蛋白和 蛋白聚糖 最近，MMP的第一个膜锚定成员 被称为膜型MMP（MT-MMP）的家族被鉴定并显示出 在多种人类癌症中以高水平表达。 基于 对MT-MMP激活明胶酶A（另一个成员）的能力的影响 具有广谱基质降解活性的MMP家族），其具有 据推测，这种新的金属蛋白酶可能作为主开关 调节癌症中组织侵袭表型的表达 细胞 然而，与MMP家族的所有成员一样，MT-MMP本身是 作为酶原合成，必须加工成其活性形式， 来表达催化活性。 目前，调节MT-MMP的因素 活化是未知的，MT-MMP的分子特征也是未知的。 明胶酶A相互作用。 此外，相关的技术复杂性 由于跨膜酶的纯化， 确定活性MT-MMP（或其活性衍生物）是否表达 另外的蛋白水解活性影响或调节 癌细胞的组织侵入特性。 为了解决这些问题， 申请人提出使用一系列分子、生物化学和细胞生物学技术， 方法I）描述控制的监管过程 ii）将MT-MMP酶原加工成其活性形式， MT-MMP依赖性明胶酶A活化的分子基础，iii） 表征膜锚定和可溶形式的酶性质 和iv）评估MT-MMP调节细胞行为的能力。 癌细胞在细胞外基质的体内样模型中。 这些 研究不仅应该为MT-MMP在 癌症进展，而且其作为新的靶点的潜在重要性 治疗干预。