Regulation of MT-MMPs by Trafficking in Cancer Cells

癌细胞贩运对 MT-MMP 的调节

• 批准号: 6831638
• 负责人: DUANQING PEI
• 金额: $ 23.83万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-05 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831638
• 关键词: Regulation; MT; MMPs; Trafficking; Cancer

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。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）与恶性癌症的进展有关，但肿瘤细胞利用这些破坏性蛋白酶的机制仍未解决。 MT-MMP 是 MMP 的一个子集，具有跨膜结构域，能够将这些酶集中在质膜上，对抗细胞外基质 (ECM) 屏障，代表了肿瘤细胞在肿瘤侵袭和转移过程中如何发挥蛋白水解活性的新范例。我们最近证明，MT1-MMP 通过网格蛋白包被的囊泡中的内吞作用来调节其在细胞表面的蛋白水解活性。我们确定其胞质结构域是内吞作用所必需的，并且其去除产生了该酶的功能获得突变体。这种内吞作用缺陷的突变体在促进前列腺癌细胞的侵袭性方面比野生型MT1-MMP更有效，这表明肿瘤细胞的侵袭性可以通过MT-MMP的运输来调节。利用 MT1-MMP 和 MT3-MMP 之间的嵌合体，我们获得了第一个证据，证明内化的 MT-MMP 可以回收回细胞表面。在本申请中，我们建议整合 MT1-MMP 和 MT3-MMP 的研究，以检验肿瘤细胞通过控制 MT-MMP 通过其细胞质域的运输来调节其侵袭性的假设。首先，我们将定义 MT1-MMP 和 MT3-MMP 从细胞表面到各个细胞内区室的运输，并表征生长因子和细胞外基质对其运输的影响。其次，我们将定义 MT1-MMP 和 MT3-MMP 的细胞质结构域在介导其运输/回收中的作用，并表征它们与细胞成分的相互作用。第三，我们将定义运输对 MT1-MMP 和 MT3-MMP 介导的细胞生长和侵袭在三维 I 型胶原基质内或通过三维 I 型胶原基质的调节作用。这些方法的结果可能会产生关于肿瘤细胞如何通过调节 MT-MMP 运输来获得生长和侵袭优势的见解，并且这些见解可能会导致用于癌症治疗和化学预防的新药物的开发。表演网站==========================================部分结束====== =======================================