Regulation of MT-MMPs by Trafficking in Cancer Cells

癌细胞贩运对 MT-MMP 的调节

基本信息

批准号：
7163439
负责人：
DUANQING PEI
金额：
$ 22.54万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-12-05 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7163439
关键词：
3-Dimensional Animal Model Back Benign Biological Models Cell Surface Receptors Cell membrane Cell surface Cells Chemoprevention Chimera organism Clathrin-Coated Vesicles Collagen Type I Cytoplasmic Tail Development Doctor of Philosophy Down-Regulation Dynamin Early Endosome Endocytosis Endopeptidases Enzymes Epigenetic Process Excision Extracellular Matrix Genetic Golgi Apparatus Growth Growth Factor Invaded Invasive Lead Lysosomes MT3 gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Matrix Metalloproteinases Measures Mediating Neoplasm Metastasis Peptide Hydrolases Pharmacotherapy Phenotype Play Process Recycling Regulation Research Personnel Role Series Specimen TFAP2A gene Testing Time Transmembrane Domain Tumor Cell Invasion cancer cell cell growth extracellular gain of function human MMP14 protein insight late endosome member membrane-type matrix metalloproteinase mutant neoplastic cell novel proMMP-2 programs trafficking

项目摘要

Our long term objective is to determine how membrane-type matrix metalloproteinases (MT-MMPs) regulate tumor invasion and metastasis. Although matrix metalloproteinases (MMPs) have been implicated in the progression of malignant cancer, the mechanism by which tumor cells deploy these destructive proteinases remains unresolved. MT-MMPs are a subset of MMPs with transmembrane domains capable of focusing these enzymes on plasma membrane against extracellular matrix (ECM) barriers, representing a novel paradigm on how tumor cells deploy proteolytic activity during tumor invasion and metastasis. We have recently demonstrated that MT1-MMP is regulated by endocytosis in clathrin- coated vesicles to control its proteolytic activity on cell surface. We established that its cytoplasmic domain is required for endocytosis and its removal gave rise to a gain-of-function mutant of this enzyme. This endocytosis-deficient mutant is more potent than wild type MT1-MMP in promoting invasiveness in prostate cancer cells, suggesting that the invasiveness of tumor cells can be regulated through the trafficking of MT-MMPs. Employing a chimera between MT1-MMP and MT3-MMP, we obtained the first evidence that internalized MT-MMPs can be recycled back to cell surface. In this application, we propose to integrate the studies of MT1-MMP and MT3- MMP to test the hypothesis that tumor cells modulate their invasiveness by controlling the trafficking of MT- MMPs through their cytoplasmic domains. First, we will define the trafficking of MT1-MMP and MT3-MMP from cell surface to various intracellular compartmetns and characterize the impact of growth factors and extracellular matrix on their trafficking. Secondly, we will define the role of cytoplasmic domains of MT1- MMP and MT3-MMP in mediating their trafficking/recycling and characterize their interactions with cellular components. Thirdly, we will define the regulatory role of trafficking on MT1-MMP and MT3-MMP mediated cell growth and invasion within or through 3-dimensional type I collagen matrix. Results from these approaches may yield insights on how tumor cells gain a growth and invasive advantage by regulating the trafficking of MT-MMPs and such insights may lead to the development of novel drugs for therapy and chemoprevention against cancer.

我们的长期目标是确定膜型基质金属蛋白酶（MT-MMP）如何调节肿瘤侵袭和转移。尽管基质金属蛋白酶（MMP）与恶性癌的进展，肿瘤细胞部署这些破坏性蛋白酶的机制仍然无法解决。 MT-MMP是具有跨膜结构域的MMP的子集这些酶在质膜上针对细胞外基质（ECM）屏障，代表一种新颖关于肿瘤细胞在肿瘤浸润和转移过程中如何部署蛋白水解活性的范式。我们有最近证明MT1-MMP受网状包包囊泡的内吞作用的调节，以控制其细胞表面上的蛋白水解活性。我们确定其胞质结构域是内吞作用所必需的它的去除引起了该酶的功能收益突变体。这种缺陷型突变体是比野生型MT1-MMP在促进前列腺癌细胞的侵袭性方面更有效，这表明肿瘤细胞的侵入性可以通过运输MT-MMP来调节。采用嵌合体在MT1-MMP和MT3-MMP之间，我们获得了内部MT-MMP的第一个证据回收回到细胞表面。在此应用中，我们建议整合MT1-MMP和MT3-的研究。 MMP检验以下假设：肿瘤细胞通过控制MT-的运输来调节其侵入性 MMP通过其细胞质结构域。首先，我们将定义MT1-MMP和MT3-MMP的贩运从细胞表面到各种细胞内c骨，并表征生长因子和细胞外基质的贩运。其次，我们将定义MT1-的细胞质结构域的作用 MMP和MT3-MMP介导其运输/回收利用并表征其与细胞的相互作用成分。第三，我们将定义贩运在MT1-MMP和MT3-MMP介导的调节作用 I型I型胶原蛋白基质内或通过3维内或通过3维内部的细胞生长和侵袭。这些结果方法可能会通过调节肿瘤细胞如何获得生长和侵入性优势的见解贩运MT-MMP和此类见解可能导致开发用于治疗和针对癌症的化学预防。