Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Nobels väg 16, SE-17177 Stockholm, Sweden.
Research Programs Unit, Genome-Scale Biology and Haartman Institute, University of Helsinki, and Helsinki University Hospital, P.O. Box 63, FI-00014 Helsinki, Finland.
Biochim Biophys Acta Mol Cell Res. 2017 Nov;1864(11 Pt A):1974-1988. doi: 10.1016/j.bbamcr.2017.04.002. Epub 2017 Apr 5.
Membrane-type matrix metalloproteases (MT-MMP) are pivotal regulators of cell invasion, growth and survival. Tethered to the cell membranes by a transmembrane domain or GPI-anchor, the six MT-MMPs can exert these functions via cell surface-associated extracellular matrix degradation or proteolytic protein processing, including shedding or release of signaling receptors, adhesion molecules, growth factors and other pericellular proteins. By interactions with signaling scaffold or cytoskeleton, the C-terminal cytoplasmic tail of the transmembrane MT-MMPs further extends their functionality to signaling or structural relay. MT-MMPs are differentially expressed in cancer. The most extensively studied MMP14/MT1-MMP is induced in various cancers along malignant transformation via pathways activated by mutations in tumor suppressors or proto-oncogenes and changes in tumor microenvironment including cellular heterogeneity, extracellular matrix composition, tissue oxygenation, and inflammation. Classically such induction involves transcriptional programs related to epithelial-to-mesenchymal transition. Besides inhibition by endogenous tissue inhibitors, MT-MMP activities are spatially and timely regulated at multiple levels by microtubular vesicular trafficking, dimerization/oligomerization, other interactions and localization in the actin-based invadosomes, in both tumor and the stroma. The functions of MT-MMPs are multifaceted within reciprocal cellular responses in the evolving tumor microenvironment, which poses the importance of these proteases beyond the central function as matrix scissors, and necessitates us to rethink MT-MMPs as dynamic signaling proteases of cancer. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman.
膜型基质金属蛋白酶（MT-MMP）是细胞侵袭、生长和存活的关键调节因子。通过跨膜结构域或 GPI 锚定与细胞膜结合，这 6 种 MT-MMP 可以通过细胞表面相关的细胞外基质降解或蛋白水解加工来发挥这些功能，包括信号受体、黏附分子、生长因子和其他细胞周围蛋白的脱落或释放。通过与信号支架或细胞骨架相互作用，跨膜 MT-MMP 的 C 端胞质尾进一步扩展了其信号或结构传递功能。MT-MMP 在癌症中表达不同。研究最广泛的 MMP14/MT1-MMP 通过肿瘤抑制因子或原癌基因突变和肿瘤微环境变化（包括细胞异质性、细胞外基质组成、组织氧合和炎症）激活的途径，在各种癌症中沿恶性转化诱导表达。经典地，这种诱导涉及与上皮间质转化相关的转录程序。除了内源性组织抑制剂的抑制作用外，MT-MMP 活性还通过微管囊泡运输、二聚化/寡聚化、其他相互作用以及在肌动蛋白基侵袭小体中的定位，在肿瘤和基质中多个水平上进行时空调节。MT-MMP 的功能在不断演变的肿瘤微环境中的细胞相互反应中是多方面的，这使得这些蛋白酶的功能不仅仅局限于作为基质剪刀的核心功能，并且需要我们重新思考 MT-MMP 作为癌症的动态信号蛋白酶。本文是由 Rafael Fridman 编辑的特刊“基质金属蛋白酶”的一部分。
