Membrane-type 1 matrix metalloproteinase: a key enzyme for tumor invasion.
Matrix metalloproteinases (MMPs) are believed to play a pivotal role in malignant behavior of cancer cells such as rapid tumor growth, invasion, and metastasis by degrading extracellular matrix (ECM). Different types of synthetic inhibitors against MMPs (MMPIs) were developed as candidates for anti-cancer therapeutics and so far clinical trials had led to no significant success. However, this does not diminish the importance of MMPs in the malignancy of cells. Details about MMPs, specifically when and how they take part in the development of cancer are necessary for more advanced application of MMPIs. In this paper, we summarize recent knowledge about membrane-type 1 matrix metalloproteinase (MT1-MMP) which is expressed on cancer cell surface as an invasion-promoting proteinase. By localizing at the leading edge of invasive cancer cells, MT1-MMP degrades components of the tissue barriers. One of the major targets is type I collagen, the most abundant ECM component. Although MT1-MMP itself cannot degrade type IV collagen in the basement membrane, it binds to and activates proMMP-2, one of the type IV collagenases. However, degradation of the ECM is not the sole function of MT1-MMP. MT1-MMP also regulates cell-ECM interaction by processing cell adhesion molecules such as CD44 and integrin alphav chain, and eventually promotes cell migration as well. In addition to the transcriptional regulation, invasion-promoting activity of the MT1-MMP is also strictly monitored at the post-translational level. Precise knowledge about the regulation will give us insight to develop new methods for treating invasive cancer patients.
Seiki
Motoharu
M
Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan. mseiki@ims.u-tokyo.ac.jp
D000818:Animals; D002465:Cell Movement; D003593:Cytoplasm / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D017434:Protein Structure, Tertiary
D018960:Hyaluronan Receptors; D020781:Matrix Metalloproteinase 1