SURFACE BINDING AND ACTIVATION OF MMP9 IN TUMOR CELLS

描述：（逐字改编自研究者摘要） 细胞外基质（ECM）的蛋白水解酶是一个关键方面， 肿瘤转移已经表明，ECM降解发生在细胞内， 表面和细胞-基质接触处。因此，我们认为， ECM降解酶的细胞表面定位促进肿瘤细胞 移民和入侵。蛋白酶的细胞表面结合也已被研究。 显示在蛋白水解活性的控制中起中心作用， 促进酶与受体、激活剂和相关物质的相互作用 印刷受体. 基质金属蛋白酶-9（MMP-9）是MMP家族的关键成员， 与恶性进展相关的ECM降解酶。 实验模型的功能研究表明， MMP-9在肿瘤转移中的作用。因此，MMP-9是一个有希望的靶点 用于新型抗转移方法。 MMP-9活性受酶原（proMMP-9）形式的活化调节 转化为具有蛋白水解活性的活性酶种类。虽然大部分 已经获得了关于proMMP-9在溶液中活化过程的信息， 在肿瘤细胞中产生活性MMP-9的机制仍然很差， 明白新的体内和体外证据表明，proMMP-9结合 对肿瘤细胞表面具有高亲和力，并定位于 肿瘤-基底膜连接。Consistent，表面相关 已经显示IV型胶原的α 2（IV）链介导 proMMP-9的各种肿瘤细胞系的表面。初步研究表明 proMMP-9表面缔合增强了活化和催化活性 同时排除与TIMP-1（一种特异性MMP-9抑制剂）的相互作用。然而，在这方面， 介导这些效应的精确的细胞和分子机制仍然存在， 下定决心。本申请中设计的研究将（1）定义 导致肿瘤细胞中proMMP-9活化的蛋白水解机制，（2） 为proMMP-9的细胞表面结合建立结构基础， (3)定义α 2（IV）在细胞表面结合和激活中的作用， proMMP-9和（4）研究细胞表面结合的作用， proMMP-9对ECM降解和肿瘤细胞侵袭的活化。结果 这些研究将解决一个新的模式，在调节MMP-9原 激活，并可能提供新的和具体的工具，以抑制MMP-9的活性 in human人tumors肿瘤.

DESCRIPTION: (adapted verbatim from the investigator's abstract) Degradation of extracellular matrices (ECM) by proteolytic enzymes is a critical aspect of tumor metastasis. It has been shown that ECM degradation occurs at the cell surface and at the cell-matrix contacts of invading cancer cells. Therefore, cell surface localization of ECM-degrading enzymes facilitates tumor cell migration and invasion. Cell surface association of proteinases has also been shown to play a central role in the control of proteolytic activity by promoting the interaction of enzymes with receptors, activators, and relevant substrates. The matrix metalloproteinase-9 (MMP-9) is a key member of the MMP family of ECM-degrading enzymes that has been associated with malignant progression. Functional studies in the experimental models have shown a direct involvement of MMP-9 in tumor metastasis. Therefore, MMP-9 represents a promising target for novel anti-metastatic approaches. MMP-9 activity is regulated by the activation of the zymogen (proMMP-9) form into an active enzyme species capable of proteolytic activity. Although much information has been gained on the process of proMMP-9 activation in solution, the mechanisms yielding active MMP-9 in tumor cells are still poorly understood. New in vivo and in vitro evidence demonstrates that proMMP-9 binds with high affinity to the surface of tumor cells and localizes at the tumor-basement membrane junctions. Consistently, a surface-associated alpha2(IV) chain of collagen IV has been shown to mediate the binding of proMMP-9 to the surface of various tumor cell lines. Preliminary studies show that surface association of proMMP-9 enhances activation and catalytic activity while precluding interactions with TIMP-1, a specific MMP-9 inhibitor. However, the precise cellular and molecular mechanisms mediating these effects remain to be determined. Studies designed in this application will (1) define the proteolytic mechanisms leading to proMMP-9 activation in tumor cells, (2) establish the structural basis for the cell surface association of proMMP-9, (3) define the role of alpha2(IV) in the cell surface binding and activation of proMMP-9 and (4) investigate the role of cell surface association and activation of proMMP-9 on ECM degradation and tumor cell invasion. The results of these studies will address a new paradigm in the regulation of proMMP-9 activation and may provide novel and specific tools to inhibit MMP-9 activity in human tumors.