This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Velasco, G. Articles by López-Otín, C. Search for Related Content PubMed PubMed Citation Articles by Velasco, G. Articles by López-Otín, C.

Human MT6-Matrix Metalloproteinase: Identification, Progelatinase A Activation, and Expression in Brain Tumors¹

Departamento de Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain [G. V., S. C., A. A. F., S. A., C. L-O.]; Laboratori de Recerca Oncologica, Servei d’Oncologia Mèdica Hospital General Universitari Vall d’Hebron, Barcelona 08035, Spain [A. M-S., J. A.]; and Department of Neurosurgery, Hyogo College of Medicine, Hyogo 663, Japan [A. N.]

The localization of proteolytic enzymes at the cell surface is a widely used strategy for facilitating tumor invasion. In this study, we have cloned a new member of the membrane-type subfamily of matrix metalloproteinases (MT-MMPs), a group of enzymes associated with tumor progression. The cloned cDNA encodes a protein of 562 amino acids with a domain organization similar to that of other MT-MMPs, including a prodomain with a cysteine switch, a catalytic domain with the zinc-binding site, a hemopexin-like domain, and a COOH-terminal extension rich in hydrophobic residues. The predicted protein sequence also contains a short insertion of basic residues located between the propeptide and the catalytic domain and involved in the proteolytic activation of MT-MMPs by furin-like enzymes. Furthermore, immunofluorescence and Western blot analysis of COS-7 cells transfected with the isolated cDNA revealed that the encoded protein is localized at the cell surface. Based on these properties, this novel human matrix metalloproteinase has been called MT6-MMP because it is the sixth identified member of this subfamily of matrix metalloproteinase. Cotransfection of expression plasmids encoding MT6-MMP and progelatinase A resulted in activation of COS-7-secreted pro-gelatinase A, as demonstrated by gelatin zymography. In contrast, transfection of progelatinase A cDNA alone did not lead to the activation of the proenzyme. Northern blot analysis of polyadenylated RNAs isolated from human tissues demonstrated that MT6-MMP is predominantly expressed in leukocytes, lung, and spleen. MT6-MMP was also detected at high levels in SW480 colon carcinoma cells as well as in some anaplastic astrocytomas and glioblastomas, but not in normal colon or brain or in meningiomas. On the basis of these results, we propose that MT6-MMP may facilitate tumor progression through its ability to activate progelatinase A at the membrane of cells from colon carcinomas or brain tumors.

This article has been cited by other articles:

				Q. Sun, C. R. Weber, A. Sohail, M. M. Bernardo, M. Toth, H. Zhao, J. R. Turner, and R. Fridman MMP25 (MT6-MMP) Is Highly Expressed in Human Colon Cancer, Promotes Tumor Growth, and Exhibits Unique Biochemical Properties J. Biol. Chem., July 27, 2007; 282(30): 21998 - 22010. [Abstract] [Full Text] [PDF]

				H. Piccard, P. E. Van den Steen, and G. Opdenakker Hemopexin domains as multifunctional liganding modules in matrix metalloproteinases and other proteins J. Leukoc. Biol., April 1, 2007; 81(4): 870 - 892. [Abstract] [Full Text] [PDF]

				C. J. Morrison and C. M. Overall TIMP Independence of Matrix Metalloproteinase (MMP)-2 Activation by Membrane Type 2 (MT2)-MMP Is Determined by Contributions of Both the MT2-MMP Catalytic and Hemopexin C Domains J. Biol. Chem., September 8, 2006; 281(36): 26528 - 26539. [Abstract] [Full Text] [PDF]

				V. Chabottaux, N. E. Sounni, C. J. Pennington, W. R. English, F. van den Brule, S. Blacher, C. Gilles, C. Munaut, E. Maquoi, C. Lopez-Otin, et al. Membrane-type 4 matrix metalloproteinase promotes breast cancer growth and metastases. Cancer Res., May 15, 2006; 66(10): 5165 - 5172. [Abstract] [Full Text] [PDF]

				J. L. English, Z. Kassiri, I. Koskivirta, S. J. Atkinson, M. Di Grappa, P. D. Soloway, H. Nagase, E. Vuorio, G. Murphy, and R. Khokha Individual Timp Deficiencies Differentially Impact Pro-MMP-2 Activation J. Biol. Chem., April 14, 2006; 281(15): 10337 - 10346. [Abstract] [Full Text] [PDF]

				A. M. Manso, L. Elsherif, S.-M. Kang, and R. S. Ross Integrins, membrane-type matrix metalloproteinases and ADAMs: Potential implications for cardiac remodeling Cardiovasc Res, February 15, 2006; 69(3): 574 - 584. [Abstract] [Full Text] [PDF]

				T. E. Van Meter, W. C. Broaddus, H. K. Rooprai, G. J. Pilkington, and H. L. Fillmore Induction of membrane-type-1 matrix metalloproteinase by epidermal growth factor-mediated signaling in gliomas Neuro-oncol, July 1, 2004; 6(3): 188 - 199. [Abstract] [PDF]

				N. E. Sounni, C. Roghi, V. Chabottaux, M. Janssen, C. Munaut, E. Maquoi, B. G. Galvez, C. Gilles, F. Frankenne, G. Murphy, et al. Up-regulation of Vascular Endothelial Growth Factor-A by Active Membrane-type 1 Matrix Metalloproteinase through Activation of Src-Tyrosine Kinases J. Biol. Chem., April 2, 2004; 279(14): 13564 - 13574. [Abstract] [Full Text] [PDF]

				X. Wang, D. Ma, J. Keski-Oja, and D. Pei Co-recycling of MT1-MMP and MT3-MMP through the Trans-Golgi Network: IDENTIFICATION OF DKV582 AS A RECYCLING SIGNAL J. Biol. Chem., March 5, 2004; 279(10): 9331 - 9336. [Abstract] [Full Text] [PDF]

				G. Velasco-Loyden, J. Arribas, and F. Lopez-Casillas The Shedding of Betaglycan Is Regulated by Pervanadate and Mediated by Membrane Type Matrix Metalloprotease-1 J. Biol. Chem., February 27, 2004; 279(9): 7721 - 7733. [Abstract] [Full Text] [PDF]

				A. M. Tester, M. Waltham, S.-J. Oh, S.-N. Bae, M. M. Bills, E. C. Walker, F. G. Kern, W. G. Stetler-Stevenson, M. E. Lippman, and E. W. Thompson Pro-Matrix Metalloproteinase-2 Transfection Increases Orthotopic Primary Growth and Experimental Metastasis of MDA-MB-231 Human Breast Cancer Cells in Nude Mice Cancer Res., January 15, 2004; 64(2): 652 - 658. [Abstract] [Full Text] [PDF]

				J. Nie and D. Pei Direct Activation of Pro-Matrix Metalloproteinase-2 by Leukolysin/Membrane-type 6 Matrix Metalloproteinase/Matrix Metalloproteinase 25 at the Asn109-Tyr Bond Cancer Res., October 15, 2003; 63(20): 6758 - 6762. [Abstract] [Full Text] [PDF]

				A. Matsuda, Y. Itoh, N. Koshikawa, T. Akizawa, I. Yana, and M. Seiki Clusterin, an Abundant Serum Factor, Is a Possible Negative Regulator of MT6-MMP/MMP-25 Produced by Neutrophils J. Biol. Chem., September 19, 2003; 278(38): 36350 - 36357. [Abstract] [Full Text] [PDF]

				M. Nakada, H. Miyamori, J. Yamashita, and H. Sato Testican 2 Abrogates Inhibition of Membrane-type Matrix Metalloproteinases by Other Testican Family Proteins Cancer Res., June 15, 2003; 63(12): 3364 - 3369. [Abstract] [Full Text] [PDF]

				R. Visse and H. Nagase Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases: Structure, Function, and Biochemistry Circ. Res., May 2, 2003; 92(8): 827 - 839. [Abstract] [Full Text] [PDF]

				R. K. Nuttall, C. J. Pennington, J. Taplin, A. Wheal, V. W. Yong, P. A. Forsyth, and D. R. Edwards Elevated Membrane-Type Matrix Metalloproteinases in Gliomas Revealed by Profiling Proteases and Inhibitors in Human Cancer Cells Mol. Cancer Res., March 1, 2003; 1(5): 333 - 345. [Abstract] [Full Text] [PDF]

				M. Pauschinger, K. Chandrasekharan, J. Li, W. Poller, M. Noutsias, C. Tschope, and H.-P. Schultheiss Inflammation and extracellular matrix protein metabolism: two sides of myocardial remodelling Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I49 - I53. [Abstract] [PDF]

				D. Luo, B. Mari, I. Stoll, and P. Anglard Alternative Splicing and Promoter Usage Generates an Intracellular Stromelysin 3 Isoform Directly Translated as an Active Matrix Metalloproteinase J. Biol. Chem., July 5, 2002; 277(28): 25527 - 25536. [Abstract] [Full Text] [PDF]

				E. Llano, G. Adam, A. M. Pendas, V. Quesada, L. M. Sanchez, I. Santamaria, S. Noselli, and C. Lopez-Otin Structural and Enzymatic Characterization of Drosophila Dm2-MMP, a Membrane-bound Matrix Metalloproteinase with Tissue-specific Expression J. Biol. Chem., June 21, 2002; 277(26): 23321 - 23329. [Abstract] [Full Text] [PDF]

				F. G. Spinale Matrix Metalloproteinases: Regulation and Dysregulation in the Failing Heart Circ. Res., March 22, 2002; 90(5): 520 - 530. [Abstract] [Full Text] [PDF]

				J. M. Mason, H.-P. Xu, S. K. Rao, A. Leask, M. Barcia, J. Shan, R. Stephenson, and S. Tabibzadeh Lefty Contributes to the Remodeling of Extracellular Matrix by Inhibition of Connective Tissue Growth Factor and Collagen mRNA Expression and Increased Proteolytic Activity in a Fibrosarcoma Model J. Biol. Chem., January 4, 2002; 277(1): 407 - 415. [Abstract] [Full Text]

				C. J. Morrison, G. S. Butler, H. F. Bigg, C. R. Roberts, P. D. Soloway, and C. M. Overall Cellular Activation of MMP-2 (Gelatinase A) by MT2-MMP Occurs via a TIMP-2-independent Pathway J. Biol. Chem., December 7, 2001; 276(50): 47402 - 47410. [Abstract] [Full Text] [PDF]

				Z. Dong, M. Katar, S. Alousi, and R. S. Berk Expression of Membrane-Type Matrix Metalloproteinases 4, 5, and 6 in Mouse Corneas Infected with P. aeruginosa Invest. Ophthalmol. Vis. Sci., December 1, 2001; 42(13): 3223 - 3227. [Abstract] [Full Text] [PDF]

				M. Nakada, A. Yamada, T. Takino, H. Miyamori, T. Takahashi, J. Yamashita, and H. Sato Suppression of Membrane-type 1 Matrix Metalloproteinase (MMP)-mediated MMP-2 Activation and Tumor Invasion by Testican 3 and Its Splicing Variant Gene Product, N-Tes Cancer Res., December 1, 2001; 61(24): 8896 - 8902. [Abstract] [Full Text] [PDF]

				W. R. English, B. Holtz, G. Vogt, V. Knauper, and G. Murphy Characterization of the Role of the "MT-loop". AN EIGHT-AMINO ACID INSERTION SPECIFIC TO PROGELATINASE A (MMP2) ACTIVATING MEMBRANE-TYPE MATRIX METALLOPROTEINASES J. Biol. Chem., November 2, 2001; 276(45): 42018 - 42026. [Abstract] [Full Text] [PDF]

				H. Hayashita-Kinoh, H. Kinoh, A. Okada, K. Komori, Y. Itoh, T. Chiba, M. Kajita, I. Yana, and M. Seiki Membrane-Type 5 Matrix Metalloproteinase Is Expressed in Differentiated Neurons and Regulates Axonal Growth Cell Growth Differ., November 1, 2001; 12(11): 573 - 580. [Abstract] [Full Text] [PDF]

				B. S. Nielsen, F. Rank, J. M. Lopez, M. Balbin, F. Vizoso, L. R. Lund, K. Dano, and C. Lopez-Otin Collagenase-3 Expression in Breast Myofibroblasts as a Molecular Marker of Transition of Ductal Carcinoma in Situ Lesions to Invasive Ductal Carcinomas Cancer Res., October 1, 2001; 61(19): 7091 - 7100. [Abstract] [Full Text] [PDF]

				J. Longin, P. Guillaumot, M.-A. Chauvin, A.-M. Morera, and B. Le Magueresse-Battistoni MT1-MMP in rat testicular development and the control of Sertoli cell proMMP-2 activation J. Cell Sci., January 6, 2001; 114(11): 2125 - 2134. [Abstract] [Full Text] [PDF]

				C. E. Brinckerhoff, J. L. Rutter, and U. Benbow Interstitial Collagenases as Markers of Tumor Progression Clin. Cancer Res., December 1, 2000; 6(12): 4823 - 4830. [Abstract] [Full Text]

				J. A. Uría and C. López-Otín Matrilysin-2, a New Matrix Metalloproteinase Expressed in Human Tumors and Showing the Minimal Domain Organization Required for Secretion, Latency, and Activity Cancer Res., September 1, 2000; 60(17): 4745 - 4751. [Abstract] [Full Text]

				K. Hotary, E. Allen, A. Punturieri, I. Yana, and S. J. Weiss Regulation of Cell Invasion and Morphogenesis in a Three-dimensional Type I Collagen Matrix by Membrane-type Matrix Metalloproteinases 1, 2, and 3 J. Cell Biol., June 12, 2000; 149(6): 1309 - 1323. [Abstract] [Full Text] [PDF]

				W. R. English, X. S. Puente, J. M. P. Freije, V. Knauper, A. Amour, A. Merryweather, C. Lopez-Otin, and G. Murphy Membrane Type 4 Matrix Metalloproteinase (MMP17) Has Tumor Necrosis Factor-alpha Convertase Activity but Does Not Activate Pro-MMP2 J. Biol. Chem., May 5, 2000; 275(19): 14046 - 14055. [Abstract] [Full Text] [PDF]

				J. Lohi, C. L. Wilson, J. D. Roby, and W. C. Parks Epilysin, a Novel Human Matrix Metalloproteinase (MMP-28) Expressed in Testis and Keratinocytes and in Response to Injury J. Biol. Chem., March 23, 2001; 276(13): 10134 - 10144. [Abstract] [Full Text] [PDF]

				H. I. Park, J. Ni, F. E. Gerkema, D. Liu, V. E. Belozerov, and Q.-X. A. Sang Identification and Characterization of Human Endometase (Matrix Metalloproteinase-26) from Endometrial Tumor J. Biol. Chem., June 30, 2000; 275(27): 20540 - 20544. [Abstract] [Full Text] [PDF]

				M. Toth, M. M. Bernardo, D. C. Gervasi, P. D. Soloway, Z. Wang, H. F. Bigg, C. M. Overall, Y. A. DeClerck, H. Tschesche, M. L. Cher, et al. Tissue Inhibitor of Metalloproteinase (TIMP)-2 Acts Synergistically with Synthetic Matrix Metalloproteinase (MMP) Inhibitors but Not with TIMP-4 to Enhance the (Membrane Type 1)-MMP-dependent Activation of Pro-MMP-2 J. Biol. Chem., December 22, 2000; 275(52): 41415 - 41423. [Abstract] [Full Text] [PDF]

				D. V. Rozanov, E. I. Deryugina, B. I. Ratnikov, E. Z. Monosov, G. N. Marchenko, J. P. Quigley, and A. Y. Strongin Mutation Analysis of Membrane Type-1 Matrix Metalloproteinase (MT1-MMP). THE ROLE OF THE CYTOPLASMIC TAIL CYS574, THE ACTIVE SITE GLU240, AND FURIN CLEAVAGE MOTIFS IN OLIGOMERIZATION, PROCESSING, AND SELF-PROTEOLYSIS OF MT1-MMP EXPRESSED IN BREAST CARCINOMA CELLS J. Biol. Chem., July 6, 2001; 276(28): 25705 - 25714. [Abstract] [Full Text] [PDF]

				T. Kang, J. Yi, A. Guo, X. Wang, C. M. Overall, W. Jiang, R. Elde, N. Borregaard, and D. Pei Subcellular Distribution and Cytokine- and Chemokine-regulated Secretion of Leukolysin/MT6-MMP/MMP-25 in Neutrophils J. Biol. Chem., June 8, 2001; 276(24): 21960 - 21968. [Abstract] [Full Text] [PDF]

				A. M. Belkin, S. S. Akimov, L. S. Zaritskaya, B. I. Ratnikov, E. I. Deryugina, and A. Y. Strongin Matrix-dependent Proteolysis of Surface Transglutaminase by Membrane-type Metalloproteinase Regulates Cancer Cell Adhesion and Locomotion J. Biol. Chem., May 18, 2001; 276(21): 18415 - 18422. [Abstract] [Full Text] [PDF]

				H. Miyamori, T. Takino, Y. Kobayashi, H. Tokai, Y. Itoh, M. Seiki, and H. Sato Claudin Promotes Activation of Pro-matrix Metalloproteinase-2 Mediated by Membrane-type Matrix Metalloproteinases J. Biol. Chem., July 20, 2001; 276(30): 28204 - 28211. [Abstract] [Full Text] [PDF]