FUNCTION OF THE MEMBRANE TYPE MATRIX METALLOPROTEINASE

描述：癌细胞通过以下途径侵袭周围组织并转移 控制蛋白水解酶的表达，使其能够降解 由细胞外基质建立的结构性屏障。一组 在被称为基质降解金属蛋白酶或MMPs的蛋白酶中， 目前被认为在癌症进展中起着重要作用，因为 这些酶可以协同作用，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 蛋白多糖。最近，MMPs的第一个膜锚定成员 该家族被鉴定为膜型基质金属蛋白酶(MT-MMPs)。 在多种人类肿瘤中高水平表达。基座 金属硫蛋白-基质金属蛋白酶激活孕激素酶A的能力 具有广谱、基质降解活性的基质金属蛋白酶家族)，它具有 据推测，这种新的金属蛋白酶可能作为主开关 调节组织侵袭性表型在癌症中的表达 细胞。然而，像所有的基质金属蛋白酶家族的成员一样，MT-基质金属氧化物本身是 作为酶原合成的，必须按顺序加工成其活性形式 来表达催化活性。目前，MT-MMPs的调控因素 金属硫蛋白-基质金属蛋白酶的分子特征尚不清楚。 孕激素酶A相互作用。此外，相关的技术复杂性 随着跨膜酶的纯化，已经排除了努力 确定活性MT-MMPs(或其活性衍生物)是否表达 额外的蛋白分解活性，影响或调节 癌细胞的组织侵袭特性。为了解决这些问题， 申请者建议使用一系列分子、生化和细胞 I)确定控制以下各项的监管程序的特征 将MT-MMP酶原加工成其活性形式，II)定义 MT-基质金属蛋白酶依赖的孕激素酶A激活的分子基础，III) 膜锚定形式和可溶性形式的酶性质表征 和iv)评估MT-MMPs调节行为的能力。 癌细胞处于类似体内的细胞外基质模型中。这些 研究不仅应该为MT-MMPs在脑内的作用提供新的见解 癌症进展，但它作为小说靶点的潜在重要性 治疗性干预。

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.