Biochemistry of MT1-MMP activation in malignancy

恶性肿瘤中 MT1-MMP 激活的生物化学

• 批准号: 8446163
• 负责人: Alex Y Strongin
• 金额: $ 36.51万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446163
• 关键词: Active Sites; Address; Adult; Agreement; Antibodies; Applied Research; Arabidopsis; Basic Science; Biochemical; Biochemistry; Bioinformatics; Biological Models; Biology; Biosensor; Cancer Biology; Cell membrane; Cell model; Cell physiology; Cell surface; Cell-Cell Adhesion; Cells; Cleaved cell; Clinical; Computer Simulation; Consensus; Data; Detection; Development; Diagnostic Neoplasm Staging; Disease; Drug Targeting; Dwarfism; Enzyme Precursors; Enzymes; Event; Exhibits; Extracellular Matrix Proteins; Funding; Gelatinase A; Genes; Grant; Human; Immunodeficient Mouse; In Vitro; Knockout Mice; Knowledge; Lead; Length; Link; Location; MMP14 gene; Malignant - descriptor; Malignant Neoplasms; Matrix Metalloproteinases; Membrane Proteins; Molecular Models; Mus; Neoplasm Metastasis; Normal Cell; Oncogenes; Pathology; Pathway interactions; Peer Review; Peptide Hydrolases; Phenotype; Plants; Play; Process; Proteolysis; Publications; Publishing; Recycling; Regulation; Research; Role; Scientist; Signal Transduction; System; Testing; Tumor Cell Biology; Tumor Cell Invasion; Tumor stage; Tumorigenicity; United States National Institutes of Health; Work; base; biochemical model; cancer cell; cell motility; cell type; design; human MMP14 protein; in vivo; inhibitor/antagonist; member; membrane-type matrix metalloproteinase; molecular modeling; neoplastic cell; novel; outcome forecast; prevent; programs; proteinase In; receptor; success; trafficking; tumor; tumor growth; tumor progression; tumor xenograft; tumorigenic

DESCRIPTION (provided by applicant): This application is a based on our previously funded 5-year project that generated over 40 peer-reviewed publications. Invasion-promoting, pro-tumorigenic MT1-MMP is implicated as the most important MMP in cancer biology and is known to play specialized roles as a modifier of cell function. There is a consensus among scientists that MT1-MMP is a key player in cell surface proteolytic events. We now know that in multiple model systems MT1-MMP acts as an oncogene, stimulates tumor cell invasion and metastasis, and takes over tumor growth control. In agreement, in humans MT1-MMP activity correlates significantly with metastases, clinical stage, and tumor size. Our knowledge of the MT1-MMP biology, however, is limited as yet especially when compared with the role this proteinase plays in malignancy. As of now, the mechanisms of MT1-MMP activation are not completely understood. As a result of our study we can now suggest that rather than exhibiting a uniform activation pathway in any cell type, invasion-promoting MT1-MMP appears to have an activation mechanism hierarchy. To increase their proteolytic arsenal, tumor cells exploit the mechanism leading to the complete inactivation of the MT1-MMP's autoinhibitory prodomain while in normal cells MT1- MMP activity is controlled by the intact prodomain that is released by furin cleavage alone. As a result, the intact prodomain prevents the potentially damaging function of pro-invasive, pro-tumorigenic MT1-MMP in the normal microenvironment. Autocatalytically activated furin plays an important role in the processing and activation of multiple proproteins including MT1-MMP and MMP-2, the downstream target of MT1-MMP. Because of its importance in cancer, MT1-MMP is a promising drug target in disease and its selective biosensor and inhibitors are urgently needed. Overall, it is obvious that additional work is needed to gain a better understanding of the MT1-MMP structural-functional relationships. Our three Specific Aims, which we have designed to achieve a better understanding of MT1-MMP are: (1) Determine the functional significance of a two-step prodomain processing mechanism of MT1-MMP activation in normal and cancer cells, (2) Design and test efficient and selective, cleavage-activated biosensors of MT1-MMP and furin (an activator of MT1-MMP), and (3) Design and evaluate the anti-tumor activity of the highly selective and potent, active site- targeting, inhibitory Fab/scFv human antibodies to MT1-MMP. The result of our proposed studies will be a thorough understanding of the many roles played by MT1-MMP and its activator, furin. Our program will use an integrated systems approach involving biochemical, molecular, cellular and computer modeling studies. We will also conduct studies using tumor xenografts in mice to validate our results gained in vitro. Our program will result in a refined understanding of how malignant cells traffic from their original location and spread throughout the body. This valuable information will lead directly to the development of novel and effective strategies for the detection, prognosis, and treatment of a broad range of malignancies.

描述（由申请人提供）：此申请是基于我们先前资助的5年项目，该项目生成了40多个同行评审出版物。 促进侵袭性的促肿瘤MT1-MMP被认为是癌症生物学中最重要的MMP，并且众所周知，它是细胞功能修饰符的专业角色。 科学家之间达成了共识，即MT1-MMP是细胞表面蛋白水解事件的关键参与者。 我们现在知道，在多种模型系统中，MT1-MMP充当癌基因，刺激肿瘤细胞的侵袭和转移，并接管肿瘤生长的控制。 一致，人类中的MT1-MMP活性与转移，临床阶段和肿瘤大小显着相关。 然而，我们对MT1-MMP生物学的了解尚未有限，尤其是与该蛋白酶在恶性肿瘤中所起的作用相比。 截至目前，尚未完全了解MT1-MMP激活的机制。 由于我们的研究结果，我们现在可以建议，而不是在任何细胞类型中表现出均匀的激活途径，而是侵袭MT1-MMP似乎具有激活机制层次结构。 为了增加其蛋白水解砷，肿瘤细胞利用了导致MT1-MMP自身抑制性抑制性的机制，而在正常细胞中，MT1-MMP活性由仅由FURIN裂解释放的完整prodomain控制。 结果，完整的prodomain阻止了正常微环境中促侵入性的二氧化肌MMP的潜在破坏功能。 自催化激活的弗林在多种普洛蛋白的加工和激活中起重要作用，包括MT1-MMP和MMP-2，这是MT1-MMP的下游靶标。 由于其在癌症中的重要性，MT1-MMP是疾病中有前途的药物靶标，其选择性生物传感器和抑制剂迫切需要。 总体而言，很明显，需要额外的工作来更好地了解MT1-MMP结构功能关系。 Our three Specific Aims, which we have designed to achieve a better understanding of MT1-MMP are: (1) Determine the functional significance of a two-step prodomain processing mechanism of MT1-MMP activation in normal and cancer cells, (2) Design and test efficient and selective, cleavage-activated biosensors of MT1-MMP and furin (an activator of MT1-MMP), and (3) Design and evaluate the高度选择性和有效的，有效的部位靶向，抑制FAB/SCFV人类抗体的抗肿瘤活性。 我们提出的研究的结果将是对MT1-MMP及其激活剂Furin扮演的许多角色的透彻理解。 我们的程序将使用涉及生化，分子，细胞和计算机建模研究的集成系统方法。 我们还将在小鼠中使用肿瘤异种移植物进行研究，以验证我们在体外获得的结果。 我们的程序将使人们对恶性细胞如何从其原始位置流动并在整个身体中传播。 这些有价值的信息将直接导致开发新颖有效的策略来检测广泛的恶性肿瘤。