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W2020973067 abstract "Membrane-type matrix metalloproteinase (MT-MMP), which we have identified recently, is unique in its transmembrane (TM) domain at the C terminus and mediates activation of pro-gelatinase A on the cell surface (Sato, H., Takino, T., Okada, Y., Cao, J., Shinagawa, A., Yamamoto, E., and Seiki, M. (1994) Nature 370, 61-65; [Medline] Takino, T., Sato, H., Yamamoto, E., and Seiki, M.(1995) Gene (Amst.) 115, 293-298). In addition to MT-MMP, a novel MMP-related cDNA of 2.1 kilobases was isolated from a human placenta cDNA library. The cDNA contains an open reading frame for a new MMP. The deduced protein composed of 604 amino acids was closely related to MT-MMP in the amino acid sequence (66% homology at the catalytic domains) and has a potential TM domain at the C terminus. Monoclonal antibodies raised against the synthetic peptide recognized a 64-kDa protein as the major product in the transfected cells. TIMP-1 fused with the potential TM domain was localized on the cell surface while native TIMP-1 is in the culture medium. Thus, we called the second membrane-type MMP, MT-MMP-2 and renamed MT-MMP, MT-MMP-1. MT-MMP-1 and −2 are thought to form a distinct membrane-type subclass in the MMP family since all the others are secreted as soluble forms. Like MT-MMP-1, expression of MT-MMP-2 induced processing of pro-gelatinase A (68-kDa in gelatin zymography) into the activated form of 62-kDa fragments through a 64-kDa intermediate form. Expression of MT-MMP-2 mRNA was at the highest levels in the brain where MT-MMP-1 was at the lowest level compared to other tissues. MT-MMP-1 and −2 are thought to be utilized for extracellular matrix turnover on the surface of cells under different genetic controls. Membrane-type matrix metalloproteinase (MT-MMP), which we have identified recently, is unique in its transmembrane (TM) domain at the C terminus and mediates activation of pro-gelatinase A on the cell surface (Sato, H., Takino, T., Okada, Y., Cao, J., Shinagawa, A., Yamamoto, E., and Seiki, M. (1994) Nature 370, 61-65; [Medline] Takino, T., Sato, H., Yamamoto, E., and Seiki, M.(1995) Gene (Amst.) 115, 293-298). In addition to MT-MMP, a novel MMP-related cDNA of 2.1 kilobases was isolated from a human placenta cDNA library. The cDNA contains an open reading frame for a new MMP. The deduced protein composed of 604 amino acids was closely related to MT-MMP in the amino acid sequence (66% homology at the catalytic domains) and has a potential TM domain at the C terminus. Monoclonal antibodies raised against the synthetic peptide recognized a 64-kDa protein as the major product in the transfected cells. TIMP-1 fused with the potential TM domain was localized on the cell surface while native TIMP-1 is in the culture medium. Thus, we called the second membrane-type MMP, MT-MMP-2 and renamed MT-MMP, MT-MMP-1. MT-MMP-1 and −2 are thought to form a distinct membrane-type subclass in the MMP family since all the others are secreted as soluble forms. Like MT-MMP-1, expression of MT-MMP-2 induced processing of pro-gelatinase A (68-kDa in gelatin zymography) into the activated form of 62-kDa fragments through a 64-kDa intermediate form. Expression of MT-MMP-2 mRNA was at the highest levels in the brain where MT-MMP-1 was at the lowest level compared to other tissues. MT-MMP-1 and −2 are thought to be utilized for extracellular matrix turnover on the surface of cells under different genetic controls. INTRODUCTIONMatrix metalloproteinases (MMPs) 1The abbreviations used are: MMPsmatrix metalloproteinasesmAbmonoclonal antibodyMT-MMPmembrane-type MMPPCRpolymerase chain reactionTIMPtissue inhibitors of metalloproteinasesTMtransmembraneDMEMDulbecco's modified Eagle's mediumkbkilobase(s). are a family of enzymes that share a common domain structure composed of propeptide, catalytic, hinge, and hemopexin-like domains (exception is MMP-7•matrilysin, which lacks a hemopexin-like domain)(3Woessner J.F.J. FASEB J. 1991; 5: 2145-2154Google Scholar, 4Birkedal-Hansen H. Moore W.G. Bodden M.K. Windsor L.J. Birkedal-Hansen B. DeCarlo A. Engler J.A. Crit. Rev. Oral Biol. Med. 1993; 4: 197-250Google Scholar). These enzymes are responsible for the turnover of extracellular matrix by degrading native macromolecules, including a variety of collagens and glycoproteins such as fibronectin and laminin, and play crucial roles in tissue remodeling during morphogenesis, wound healing, angiogenesis, and also in many pathological conditions such as tumor invasion and rheumatoid arthritis(5Matrisian L.M. Trends Genet. 1990; 6: 121-125Google Scholar, 6Liotta L.A. Steeg P.S. Stetler-Stevenson W.G. Cell. 1991; 64: 327-336Google Scholar, 7Matrisian L.M. BioEssays. 1992; 14: 455-463Google Scholar, 8Sato H. Kida Y. Mai M. Endo Y. Sasaki T. Tanaka J. Seiki M. Oncogene. 1992; 7: 77-83Google Scholar, 9Tsuchiya Y. Sato H. Endo Y. Okada Y. Mai M. Sasaki T. Seiki M. Cancer Res. 1993; 53: 1397-1402Google Scholar, 10Tsuchiya Y. Endo Y. Sato H. Okada Y. Mai M. Sasaki T. Seiki M. Int. J. Cancer. 1994; 56: 46-51Google Scholar). 11 MMPs encoded by different genes are known as the MMP family members, and they have different substrate specificity against extracellular matrix macromolecules. 10 of them are produced by cells as a soluble zymogen form, but the last one, which we recently discovered, has a transmembrane domain at the C terminus and is expressed as a membrane protein(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar, 2Takino T. Sato H. Yamamoto E. Seiki M. Gene (Amst.). 1995; 115: 293-298Google Scholar, 11Cao J. Sato H. Takino T. Seiki M. J. Biol. Chem. 1995; 270: 801-805Google Scholar). Thus, we called this ectoenzyme membrane-type MMP (MT-MMP).All of the MMPs are expressed as inactive zymogens and need proteolytic activation for them to function. Although serine proteases such as plasmin, neutrophil elastase, and trypsin can activate several MMP zymogens in a test tube(12He C.S. Wilhelm S.M. Pentland A.P. Marmer B.L. Grant G.A. Eisen A.Z. Goldberg G.I. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 2632-2636Google Scholar, 13Nagase H. Enghild J.J. Suzuki K. Salvesen G. Biochemistry. 1990; 29: 5783-5789Google Scholar), little is known about the activators in tissue. MMP-2•gelatinase A cannot be activated by these serine proteinases (14Okada Y. Morodomi T. Enghild J.J. Suzuki K. Yasui A. Nakanishi I. Salvesen G. Nagase H. Eur. J. Biochem. 1990; 194: 721-730Google Scholar, 15Nagase H. Suzuki K. Morodomi T. Enghild J.J. Salvesen G. Matrix. 1992; 1: 237-244Google Scholar) but is activated on the surfaces of fibroblasts (16Ward R.V. Atkinson S.J. Slocombe P.M. Docherty A.J. Reynolds J.J. Murphy G. Biochim. Biophys. Acta. 1991; 1079: 242-246Google Scholar) and tumor cell lines treated with 12-O-tetradecanoylphorbol-13-acetate or concanavalin A (17Brown P.D. Levy A.T. Margulies I.M. Liotta L.A. Stetler-Stevenson W.G. Cancer Res. 1990; 50: 6184-6191Google Scholar, 18Azzam H.S. Arand G. Lippman M.E. Thompson E.W. J. Natl. Cancer Inst. 1993; 85: 1758-1764Google Scholar, 19Strongin A.Y. Marmer B.L. Grant G.A. Goldberg G.I. J. Biol. Chem. 1993; 268: 14033-14039Google Scholar). Thus, a unique activator on the cell surface was expected to be responsible for gelatinase A activation, and it turned out to be MT-MMP. Expression of MT-MMP in the transfected cells induced specific activation of gelatinase A in a cell-mediated manner(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar). Appearance of the activated form of gelatinase A in the tissue is also a characteristic feature of invasive carcinomas(20Brown P.D. Bloxidge R.E. Anderson E. Howell A. Clin. Exp. Metastasis. 1993; 11: 183-189Google Scholar, 21Brown P.D. Bloxidge R.E. Stuart N.S.A. Gatter K.C. Carmichael J. J. Natl. Cancer Inst. 1993; 85: 574-578Google Scholar). Expression of MT-MMP was detected there, and the product was immunolocalized in and on the carcinoma cells(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar). Since gelatinase A is an important enzyme for basement membrane invasion by degrading type IV collagen, MT-MMP on the tumor cell surface is thought to play a critical role in the invasive phenotype of tumor cells.MT-MMP cDNA was isolated from a human placenta cDNA library using a MMP-related gene fragment as a probe(2Takino T. Sato H. Yamamoto E. Seiki M. Gene (Amst.). 1995; 115: 293-298Google Scholar). The probe with a possible new MMP gene sequence was obtained from the amplified cDNA fragments by polymerase chain reaction (PCR) using degenerate oligonucleotide primers corresponding to the conserved sequences within the MMP family. The structural characteristic of MT-MMP is the transmembrane domain at the C terminus and two more additional insertions. One is the insertion of 8 amino acids in the catalytic domain, and the other is the insertion of 11 amino acids between the propeptide and the catalytic domain. MMP-11•stromelysin-3 (22Basset P. Bellocq J.P. Wolf C. Stoll I. Hutin P. Limacher J.M. Podhajcer O.L. Chenard M.P. Rio M.C. Chambon P. Nature. 1990; 348: 699-704Google Scholar) has a similar insertion of 10 amino acids between propeptide and catalytic domain, and RXKR sequences, potential recognition sites for subtilisin-like processing enzymes(23Hosaka M. Nagahama M. Kim W.S. Watanabe T. Hatsuzawa K. Ikemizu J. Murakami K. Nakayama K. J. Biol. Chem. 1991; 266: 12127-12130Google Scholar), are conserved between them. No insertion corresponding to the 8 amino acids of MT-MMP was found in the other members of the MMP family.Both MT-MMP and stromelysin-3 were identified by cDNA cloning instead of the conventional biochemical purification of the enzymes. Thus, new MMP members may be obtained further by survey of the MMP-related genes. To identify yet unknown MMP members, we extended our previous study to survey the MMP-related cDNAs amplified from various human tissues by reverse transcription-PCR. In this study, we identified a fragment of another new MMP-related gene from a human melanoma tissue. This fragment was used as a probe to screen a human placenta cDNA library, and a cDNA fragment that encodes a new MMP having a TM domain at the C terminus was obtained. Thus, MT-MMPs form a distinct subgroup in the MMP family.DISCUSSIONIn addition to MT-MMP-1 (MT-MMP in the previous paper), which we previously reported(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar, 2Takino T. Sato H. Yamamoto E. Seiki M. Gene (Amst.). 1995; 115: 293-298Google Scholar), we identified a new MMP gene that was expressed in a human oral malignant melanoma and a human placenta. The isolated 2.1-kilobase pair cDNA contained a sufficient coding frame for MT-MMP-2. However, the transcript in tissues or cell lines was at 12 kb in size. Since the cDNA lacks the typical polyadenylation signal (AATAAA), the 3′-non-coding region of the gene is thought to be missing in the cloned fragment. MT-MMP-1 and −2 are approximately the same in their molecular weights, but they are encoded by 4.5- and 12-kb transcripts, respectively. The most plausible explanation for the difference of the mRNA sizes is the different length of non-coding regions at their 3′-ends.MT-MMP-2 is the most closely related to MT-MMP-1 in the amino acid sequence (66% homology at the catalytic domain) and in the characteristic insertions compared to other MMPs. These insertions may be important for their function and regulation. For example, the first insertions (IS-1) between the propeptide and catalytic domain contain the conserved RXKR sequences. A similar insertion also exists in stromelysin-3 but not in others (Fig. 2B). These sequences may be the recognition site for processing, since immediately downstream of the RXKR sequences is the reported N terminus of the processed forms of stromelysin 3 and MT-MMP-1(34Murphy G. Segain J.P. O'Shea M. Cockett M. Ioannou C. Lefebvre O. Chambon P. Basset P. J Biol Chem. 1993; 268: 15435-15441Google Scholar, 35Strongin A.Y. Collier I. Bannikov G. Marmer B.L. Grant G.A. Goldberg G.I. J. Biol. Chem. 1995; 270: 5331-5338Google Scholar). Since RXKR is the consensus sequence for subtilisin-like enzymes, autocatalytic activation mechanism, which is common for other MMPs, may not be applicable for these three MMPs. Indeed, 4-aminophenylmercuric acetate or SDS that induces autocatalytic activation of pro-MMPs cannot activate stromelysin-3 and MT-MMPs.There exist 8 amino acid insertions (IS-2) in the catalytic domains of MT-MMP-1 and −2 at the same position. Three of the eight amino acids at both ends were conserved. Although the significance of this insertion is not clear, it may modulate substrate specificity of the enzymes from its position in the catalytic domain like the gelatin-binding domain of two gelatinases(36Murphy G. Nguyen Q. Cockett M.I. Atkinson S.J. Allan J.A. Knight C.G. Willenbrock F. Docherty A.J. J. Biol. Chem. 1994; 269: 6632-6636Google Scholar).Additional sequences (IS-3) containing the TM domains are found downstream of the hemopexin-like domains of MT-MMPs. Both MT-MMPs are expressed as membrane proteins embedded into the plasma membrane through the TM domains at the C terminus. Thus, these two MMPs form a unique membrane-type subclass in the MMP family, while the others are expressed as a soluble form. We previously aligned the most C-terminal portion of the cysteine residue of MT-MMP-1 to that of the hemopexin-like domain of other MMPs and thought that the TM domain is an insertion in the hemopexin-like domain(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar, 2Takino T. Sato H. Yamamoto E. Seiki M. Gene (Amst.). 1995; 115: 293-298Google Scholar). However, it is more appropriate that the IS-3 locate downstream of the hemopexin-like domains of MT-MMP-1 and −2 rather than splitting the domain as shown in the alignment in Fig. 2. With this alignment, it becomes possible for MT-MMPs to form a cysteine bridge in the hemopexin-like domain, the conserved structure among the MMPs, outside of the cells.Expression of MT-MMP-2 in cells, like that of MT-MMP-1, induced activation of the pro-gelatinase A to the fully activated form (62 kDa) through the intermediate form (64 kDa). Thus, both MT-MMPs have similar biochemical activities at least in part, though it remains to be elucidated whether these MT-MMPs have different substrate specificity or not. If both MT-MMPs are similar in function, why are two separate genes required for the organism? The organism may have to utilize these MT-MMPs in different tissue environment or situations. Consistent with this idea, the tissue distribution of the MT-MMP-1 and MT-MMP-2 mRNAs was different in the human tissues. In contrast to MT-MMP-1, which is expressed widely in various tissues, MT-MMP-2 is expressed in only restricted tissues such as brain, heart, and placenta. In particular, brain tissue expresses MT-MMP-2 at the highest level but expresses MT-MMP-1 at the lowest level. The high level expression of MT-MMP-2 in brain may suggest a specific role of the product in the central nervous system. In cell lines, squamous cell carcinoma OSC-19 and human embryonal lung fibroblasts express MT-MMP-1 mRNA at higher levels but MT-MMP-2 mRNA at lower levels. The reverse was also the case; the MT-MMP-1 mRNA level was low in T24 cells where MT-MMP-2 mRNA was expressed predominantly.Since MT-MMP-2 was originally detected in oral malignant melanoma, whether MT-MMP-2 is also involved in activation of gelatinase A in tumor tissues like MT-MMP-1 is of interest. Our preliminary findings with lung carcinomas where MT-MMP-1 was overexpressed indicated that MT-MMP-2 was not expressed frequently there. 2T. Takino, H. Sato, A. Shinagawa, and M. Seiki, unpublished results. In addition to the activation of pro-gelatinase A, some of the proteins, such as β-amyloid precursor protein, tumor necrosis factor-α, and V-2 vasopressin receptor, are reported to be processed on the cell membrane by MMP-like activities(37Miyazaki K. Hasegawa M. Funahashi K. Umeda M. Nature. 1993; 362: 839-841Google Scholar, 38Mohler K.M. Sleath P.R. Fitzner J.N. Cerretti D.P. Alderson M. Kerwar S.S. Torrance D.S. Otten-Evans C. Greenstreet T. Weerawarna K. Kronheim S.R. Petersen M. Gerhart M. Kozlosky C.J. March C.J. Black R.A. Nature. 1994; 370: 218-220Google Scholar, 39Gearing A.J. Beckett P. Christodoulou M. Churchill M. Clements J. Davidson A.H. Drummond A.H. Galloway W.A. Gilbert R. Gordon J.L. Leber T.M. Mangan M. Miller K. Nayee P. Owen K. Patel S. Thomas W. Well G. Wood L.M. Wooley K. Nature. 1994; 370: 555-557Google Scholar, 40Kojro E. Fahrenholz F. J. Biol. Chem. 1995; 270: 6476-6481Google Scholar). MT-MMPs may be responsible for the processing of many biologically important proteins on the cell surface as a regulator. These possibilities remain to be examined.In this study, we reported MT-MMP-2 as a new member of the MMP family. Since both MT-MMP-1 and −2 have TM domains at the C terminus, we proposed a new subclass for MT-MMPs in the MMP family. Studies of MT-MMPs should provide clues to understand the cell surface events controlling extracellular matrix turnover and diverse biological responses. INTRODUCTIONMatrix metalloproteinases (MMPs) 1The abbreviations used are: MMPsmatrix metalloproteinasesmAbmonoclonal antibodyMT-MMPmembrane-type MMPPCRpolymerase chain reactionTIMPtissue inhibitors of metalloproteinasesTMtransmembraneDMEMDulbecco's modified Eagle's mediumkbkilobase(s). are a family of enzymes that share a common domain structure composed of propeptide, catalytic, hinge, and hemopexin-like domains (exception is MMP-7•matrilysin, which lacks a hemopexin-like domain)(3Woessner J.F.J. FASEB J. 1991; 5: 2145-2154Google Scholar, 4Birkedal-Hansen H. Moore W.G. Bodden M.K. Windsor L.J. Birkedal-Hansen B. DeCarlo A. Engler J.A. Crit. Rev. Oral Biol. Med. 1993; 4: 197-250Google Scholar). These enzymes are responsible for the turnover of extracellular matrix by degrading native macromolecules, including a variety of collagens and glycoproteins such as fibronectin and laminin, and play crucial roles in tissue remodeling during morphogenesis, wound healing, angiogenesis, and also in many pathological conditions such as tumor invasion and rheumatoid arthritis(5Matrisian L.M. Trends Genet. 1990; 6: 121-125Google Scholar, 6Liotta L.A. Steeg P.S. Stetler-Stevenson W.G. Cell. 1991; 64: 327-336Google Scholar, 7Matrisian L.M. BioEssays. 1992; 14: 455-463Google Scholar, 8Sato H. Kida Y. Mai M. Endo Y. Sasaki T. Tanaka J. Seiki M. Oncogene. 1992; 7: 77-83Google Scholar, 9Tsuchiya Y. Sato H. Endo Y. Okada Y. Mai M. Sasaki T. Seiki M. Cancer Res. 1993; 53: 1397-1402Google Scholar, 10Tsuchiya Y. Endo Y. Sato H. Okada Y. Mai M. Sasaki T. Seiki M. Int. J. Cancer. 1994; 56: 46-51Google Scholar). 11 MMPs encoded by different genes are known as the MMP family members, and they have different substrate specificity against extracellular matrix macromolecules. 10 of them are produced by cells as a soluble zymogen form, but the last one, which we recently discovered, has a transmembrane domain at the C terminus and is expressed as a membrane protein(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar, 2Takino T. Sato H. Yamamoto E. Seiki M. Gene (Amst.). 1995; 115: 293-298Google Scholar, 11Cao J. Sato H. Takino T. Seiki M. J. Biol. Chem. 1995; 270: 801-805Google Scholar). Thus, we called this ectoenzyme membrane-type MMP (MT-MMP).All of the MMPs are expressed as inactive zymogens and need proteolytic activation for them to function. Although serine proteases such as plasmin, neutrophil elastase, and trypsin can activate several MMP zymogens in a test tube(12He C.S. Wilhelm S.M. Pentland A.P. Marmer B.L. Grant G.A. Eisen A.Z. Goldberg G.I. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 2632-2636Google Scholar, 13Nagase H. Enghild J.J. Suzuki K. Salvesen G. Biochemistry. 1990; 29: 5783-5789Google Scholar), little is known about the activators in tissue. MMP-2•gelatinase A cannot be activated by these serine proteinases (14Okada Y. Morodomi T. Enghild J.J. Suzuki K. Yasui A. Nakanishi I. Salvesen G. Nagase H. Eur. J. Biochem. 1990; 194: 721-730Google Scholar, 15Nagase H. Suzuki K. Morodomi T. Enghild J.J. Salvesen G. Matrix. 1992; 1: 237-244Google Scholar) but is activated on the surfaces of fibroblasts (16Ward R.V. Atkinson S.J. Slocombe P.M. Docherty A.J. Reynolds J.J. Murphy G. Biochim. Biophys. Acta. 1991; 1079: 242-246Google Scholar) and tumor cell lines treated with 12-O-tetradecanoylphorbol-13-acetate or concanavalin A (17Brown P.D. Levy A.T. Margulies I.M. Liotta L.A. Stetler-Stevenson W.G. Cancer Res. 1990; 50: 6184-6191Google Scholar, 18Azzam H.S. Arand G. Lippman M.E. Thompson E.W. J. Natl. Cancer Inst. 1993; 85: 1758-1764Google Scholar, 19Strongin A.Y. Marmer B.L. Grant G.A. Goldberg G.I. J. Biol. Chem. 1993; 268: 14033-14039Google Scholar). Thus, a unique activator on the cell surface was expected to be responsible for gelatinase A activation, and it turned out to be MT-MMP. Expression of MT-MMP in the transfected cells induced specific activation of gelatinase A in a cell-mediated manner(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar). Appearance of the activated form of gelatinase A in the tissue is also a characteristic feature of invasive carcinomas(20Brown P.D. Bloxidge R.E. Anderson E. Howell A. Clin. Exp. Metastasis. 1993; 11: 183-189Google Scholar, 21Brown P.D. Bloxidge R.E. Stuart N.S.A. Gatter K.C. Carmichael J. J. Natl. Cancer Inst. 1993; 85: 574-578Google Scholar). Expression of MT-MMP was detected there, and the product was immunolocalized in and on the carcinoma cells(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar). Since gelatinase A is an important enzyme for basement membrane invasion by degrading type IV collagen, MT-MMP on the tumor cell surface is thought to play a critical role in the invasive phenotype of tumor cells.MT-MMP cDNA was isolated from a human placenta cDNA library using a MMP-related gene fragment as a probe(2Takino T. Sato H. Yamamoto E. Seiki M. Gene (Amst.). 1995; 115: 293-298Google Scholar). The probe with a possible new MMP gene sequence was obtained from the amplified cDNA fragments by polymerase chain reaction (PCR) using degenerate oligonucleotide primers corresponding to the conserved sequences within the MMP family. The structural characteristic of MT-MMP is the transmembrane domain at the C terminus and two more additional insertions. One is the insertion of 8 amino acids in the catalytic domain, and the other is the insertion of 11 amino acids between the propeptide and the catalytic domain. MMP-11•stromelysin-3 (22Basset P. Bellocq J.P. Wolf C. Stoll I. Hutin P. Limacher J.M. Podhajcer O.L. Chenard M.P. Rio M.C. Chambon P. Nature. 1990; 348: 699-704Google Scholar) has a similar insertion of 10 amino acids between propeptide and catalytic domain, and RXKR sequences, potential recognition sites for subtilisin-like processing enzymes(23Hosaka M. Nagahama M. Kim W.S. Watanabe T. Hatsuzawa K. Ikemizu J. Murakami K. Nakayama K. J. Biol. Chem. 1991; 266: 12127-12130Google Scholar), are conserved between them. No insertion corresponding to the 8 amino acids of MT-MMP was found in the other members of the MMP family.Both MT-MMP and stromelysin-3 were identified by cDNA cloning instead of the conventional biochemical purification of the enzymes. Thus, new MMP members may be obtained further by survey of the MMP-related genes. To identify yet unknown MMP members, we extended our previous study to survey the MMP-related cDNAs amplified from various human tissues by reverse transcription-PCR. In this study, we identified a fragment of another new MMP-related gene from a human melanoma tissue. This fragment was used as a probe to screen a human placenta cDNA library, and a cDNA fragment that encodes a new MMP having a TM domain at the C terminus was obtained. Thus, MT-MMPs form a distinct subgroup in the MMP family. Matrix metalloproteinases (MMPs) 1The abbreviations used are: MMPsmatrix metalloproteinasesmAbmonoclonal antibodyMT-MMPmembrane-type MMPPCRpolymerase chain reactionTIMPtissue inhibitors of metalloproteinasesTMtransmembraneDMEMDulbecco's modified Eagle's mediumkbkilobase(s). are a family of enzymes that share a common domain structure composed of propeptide, catalytic, hinge, and hemopexin-like domains (exception is MMP-7•matrilysin, which lacks a hemopexin-like domain)(3Woessner J.F.J. FASEB J. 1991; 5: 2145-2154Google Scholar, 4Birkedal-Hansen H. Moore W.G. Bodden M.K. Windsor L.J. Birkedal-Hansen B. DeCarlo A. Engler J.A. Crit. Rev. Oral Biol. Med. 1993; 4: 197-250Google Scholar). These enzymes are responsible for the turnover of extracellular matrix by degrading native macromolecules, including a variety of collagens and glycoproteins such as fibronectin and laminin, and play crucial roles in tissue remodeling during morphogenesis, wound healing, angiogenesis, and also in many pathological conditions such as tumor invasion and rheumatoid arthritis(5Matrisian L.M. Trends Genet. 1990; 6: 121-125Google Scholar, 6Liotta L.A. Steeg P.S. Stetler-Stevenson W.G. Cell. 1991; 64: 327-336Google Scholar, 7Matrisian L.M. BioEssays. 1992; 14: 455-463Google Scholar, 8Sato H. Kida Y. Mai M. Endo Y. Sasaki T. Tanaka J. Seiki M. Oncogene. 1992; 7: 77-83Google Scholar, 9Tsuchiya Y. Sato H. Endo Y. Okada Y. Mai M. Sasaki T. Seiki M. Cancer Res. 1993; 53: 1397-1402Google Scholar, 10Tsuchiya Y. Endo Y. Sato H. Okada Y. Mai M. Sasaki T. Seiki M. Int. J. Cancer. 1994; 56: 46-51Google Scholar). 11 MMPs encoded by different genes are known as the MMP family members, and they have different substrate specificity against extracellular matrix macromolecules. 10 of them are produced by cells as a soluble zymogen form, but the last one, which we recently discovered, has a transmembrane domain at the C terminus and is expressed as a membrane protein(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar, 2Takino T. Sato H. Yamamoto E. Seiki M. Gene (Amst.). 1995; 115: 293-298Google Scholar, 11Cao J. Sato H. Takino T. Seiki M. J. Biol. Chem. 1995; 270: 801-805Google Scholar). Thus, we called this ectoenzyme membrane-type MMP (MT-MMP). matrix metalloproteinases monoclonal antibody membrane-type MMP polymerase chain reaction tissue inhibitors of metalloproteinases transmembrane Dulbecco's modified Eagle's medium kilobase(s). All of the MMPs are expressed as inactive zymogens and need proteolytic activation for them to function. Although serine proteases such as plasmin, neutrophil elastase, and trypsin can activate several MMP zymogens in a test tube(12He C.S. Wilhelm S.M. Pentland A.P. Marmer B.L. Grant G.A. Eisen A.Z. Goldberg G.I. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 2632-2636Google Scholar, 13Nagase H. Enghild J.J. Suzuki K. Salvesen G. Biochemistry. 1990; 29: 5783-5789Google Scholar), little is known about the activators in tissue. MMP-2•gelatinase A cannot be activated by these serine proteinases (14Okada Y. Morodomi T. Enghild J.J. Suzuki K. Yasui A. Nakanishi I. Salvesen G. Nagase H. Eur. J. Biochem. 1990; 194: 721-730Google Scholar, 15Nagase H. Suzuki K. Morodomi T. Enghild J.J. Salvesen G. Matrix. 1992; 1: 237-244Google Scholar) but is activated on the surfaces of fibroblasts (16Ward R.V. Atkinson S.J. Slocombe P.M. Docherty A.J. Reynolds J.J. Murphy G. Biochim. Biophys. Acta. 1991; 1079: 242-246Google Scholar) and tumor cell lines treated with 12-O-tetradecanoylphorbol-13-acetate or concanavalin A (17Brown P.D. Levy A.T. Margulies I.M. Liotta L.A. Stetler-Stevenson W.G. Cancer Res. 1990; 50: 6184-6191Google Scholar, 18Azzam H.S. Arand G. Lippman M.E. Thompson E.W. J. Natl. Cancer Inst. 1993; 85: 1758-1764Google Scholar, 19Strongin A.Y. Marmer B.L. Grant G.A. Goldberg G.I. J. Biol. Chem. 1993; 268: 14033-14039Google Scholar). Thus, a unique activator on the cell surface was expected to be responsible for gelatinase A activation, and it turned out to be MT-MMP. Expression of MT-MMP in the transfected cells induced specific activation of gelatinase A in a cell-mediated manner(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar). Appearance of the activated form of gelatinase A in the tissue is also a characteristic feature of invasive carcinomas(20Brown P.D. Bloxidge R.E. Anderson E. Howell A. Clin. Exp. Metastasis. 1993; 11: 183-189Google Scholar, 21Brown P.D. Bloxidge R.E. Stuart N.S.A. Gatter K.C. Carmichael J. J. Natl. Cancer Inst. 1993; 85: 574-578Google Scholar). Expression of MT-MMP was detected there, and the product was immunolocalized in and on the carcinoma cells(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar). Since gelatinase A is an important enzyme for basement membrane invasion by degrading type IV collagen, MT-MMP on the tumor cell surface is thought to play a critical role in the invasive phenotype of tumor cells. MT-MMP cDNA was isolated from a human placenta cDNA library using a MMP-related gene fragment as a probe(2Takino T. Sato H. Yamamoto E. Seiki M. Gene (Amst.). 1995; 115: 293-298Google Scholar). The probe with a possible new MMP gene sequence was obtained from the amplified cDNA fragments by polymerase chain reaction (PCR) using degenerate oligonucleotide primers corresponding to the conserved sequences within the MMP family. The structural characteristic of MT-MMP is the transmembrane domain at the C terminus and two more additional insertions. One is the insertion of 8 amino acids in the catalytic domain, and the other is the insertion of 11 amino acids between the propeptide and the catalytic domain. MMP-11•stromelysin-3 (22Basset P. Bellocq J.P. Wolf C. Stoll I. Hutin P. Limacher J.M. Podhajcer O.L. Chenard M.P. Rio M.C. Chambon P. Nature. 1990; 348: 699-704Google Scholar) has a similar insertion of 10 amino acids between propeptide and catalytic domain, and RXKR sequences, potential recognition sites for subtilisin-like processing enzymes(23Hosaka M. Nagahama M. Kim W.S. Watanabe T. Hatsuzawa K. Ikemizu J. Murakami K. Nakayama K. J. Biol. Chem. 1991; 266: 12127-12130Google Scholar), are conserved between them. No insertion corresponding to the 8 amino acids of MT-MMP was found in the other members of the MMP family. Both MT-MMP and stromelysin-3 were identified by cDNA cloning instead of the conventional biochemical purification of the enzymes. Thus, new MMP members may be obtained further by survey of the MMP-related genes. To identify yet unknown MMP members, we extended our previous study to survey the MMP-related cDNAs amplified from various human tissues by reverse transcription-PCR. In this study, we identified a fragment of another new MMP-related gene from a human melanoma tissue. This fragment was used as a probe to screen a human placenta cDNA library, and a cDNA fragment that encodes a new MMP having a TM domain at the C terminus was obtained. Thus, MT-MMPs form a distinct subgroup in the MMP family. DISCUSSIONIn addition to MT-MMP-1 (MT-MMP in the previous paper), which we previously reported(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar, 2Takino T. Sato H. Yamamoto E. Seiki M. Gene (Amst.). 1995; 115: 293-298Google Scholar), we identified a new MMP gene that was expressed in a human oral malignant melanoma and a human placenta. The isolated 2.1-kilobase pair cDNA contained a sufficient coding frame for MT-MMP-2. However, the transcript in tissues or cell lines was at 12 kb in size. Since the cDNA lacks the typical polyadenylation signal (AATAAA), the 3′-non-coding region of the gene is thought to be missing in the cloned fragment. MT-MMP-1 and −2 are approximately the same in their molecular weights, but they are encoded by 4.5- and 12-kb transcripts, respectively. The most plausible explanation for the difference of the mRNA sizes is the different length of non-coding regions at their 3′-ends.MT-MMP-2 is the most closely related to MT-MMP-1 in the amino acid sequence (66% homology at the catalytic domain) and in the characteristic insertions compared to other MMPs. These insertions may be important for their function and regulation. For example, the first insertions (IS-1) between the propeptide and catalytic domain contain the conserved RXKR sequences. A similar insertion also exists in stromelysin-3 but not in others (Fig. 2B). These sequences may be the recognition site for processing, since immediately downstream of the RXKR sequences is the reported N terminus of the processed forms of stromelysin 3 and MT-MMP-1(34Murphy G. Segain J.P. O'Shea M. Cockett M. Ioannou C. Lefebvre O. Chambon P. Basset P. J Biol Chem. 1993; 268: 15435-15441Google Scholar, 35Strongin A.Y. Collier I. Bannikov G. Marmer B.L. Grant G.A. Goldberg G.I. J. Biol. Chem. 1995; 270: 5331-5338Google Scholar). Since RXKR is the consensus sequence for subtilisin-like enzymes, autocatalytic activation mechanism, which is common for other MMPs, may not be applicable for these three MMPs. Indeed, 4-aminophenylmercuric acetate or SDS that induces autocatalytic activation of pro-MMPs cannot activate stromelysin-3 and MT-MMPs.There exist 8 amino acid insertions (IS-2) in the catalytic domains of MT-MMP-1 and −2 at the same position. Three of the eight amino acids at both ends were conserved. Although the significance of this insertion is not clear, it may modulate substrate specificity of the enzymes from its position in the catalytic domain like the gelatin-binding domain of two gelatinases(36Murphy G. Nguyen Q. Cockett M.I. Atkinson S.J. Allan J.A. Knight C.G. Willenbrock F. Docherty A.J. J. Biol. Chem. 1994; 269: 6632-6636Google Scholar).Additional sequences (IS-3) containing the TM domains are found downstream of the hemopexin-like domains of MT-MMPs. Both MT-MMPs are expressed as membrane proteins embedded into the plasma membrane through the TM domains at the C terminus. Thus, these two MMPs form a unique membrane-type subclass in the MMP family, while the others are expressed as a soluble form. We previously aligned the most C-terminal portion of the cysteine residue of MT-MMP-1 to that of the hemopexin-like domain of other MMPs and thought that the TM domain is an insertion in the hemopexin-like domain(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar, 2Takino T. Sato H. Yamamoto E. Seiki M. Gene (Amst.). 1995; 115: 293-298Google Scholar). However, it is more appropriate that the IS-3 locate downstream of the hemopexin-like domains of MT-MMP-1 and −2 rather than splitting the domain as shown in the alignment in Fig. 2. With this alignment, it becomes possible for MT-MMPs to form a cysteine bridge in the hemopexin-like domain, the conserved structure among the MMPs, outside of the cells.Expression of MT-MMP-2 in cells, like that of MT-MMP-1, induced activation of the pro-gelatinase A to the fully activated form (62 kDa) through the intermediate form (64 kDa). Thus, both MT-MMPs have similar biochemical activities at least in part, though it remains to be elucidated whether these MT-MMPs have different substrate specificity or not. If both MT-MMPs are similar in function, why are two separate genes required for the organism? The organism may have to utilize these MT-MMPs in different tissue environment or situations. Consistent with this idea, the tissue distribution of the MT-MMP-1 and MT-MMP-2 mRNAs was different in the human tissues. In contrast to MT-MMP-1, which is expressed widely in various tissues, MT-MMP-2 is expressed in only restricted tissues such as brain, heart, and placenta. In particular, brain tissue expresses MT-MMP-2 at the highest level but expresses MT-MMP-1 at the lowest level. The high level expression of MT-MMP-2 in brain may suggest a specific role of the product in the central nervous system. In cell lines, squamous cell carcinoma OSC-19 and human embryonal lung fibroblasts express MT-MMP-1 mRNA at higher levels but MT-MMP-2 mRNA at lower levels. The reverse was also the case; the MT-MMP-1 mRNA level was low in T24 cells where MT-MMP-2 mRNA was expressed predominantly.Since MT-MMP-2 was originally detected in oral malignant melanoma, whether MT-MMP-2 is also involved in activation of gelatinase A in tumor tissues like MT-MMP-1 is of interest. Our preliminary findings with lung carcinomas where MT-MMP-1 was overexpressed indicated that MT-MMP-2 was not expressed frequently there. 2T. Takino, H. Sato, A. Shinagawa, and M. Seiki, unpublished results. In addition to the activation of pro-gelatinase A, some of the proteins, such as β-amyloid precursor protein, tumor necrosis factor-α, and V-2 vasopressin receptor, are reported to be processed on the cell membrane by MMP-like activities(37Miyazaki K. Hasegawa M. Funahashi K. Umeda M. Nature. 1993; 362: 839-841Google Scholar, 38Mohler K.M. Sleath P.R. Fitzner J.N. Cerretti D.P. Alderson M. Kerwar S.S. Torrance D.S. Otten-Evans C. Greenstreet T. Weerawarna K. Kronheim S.R. Petersen M. Gerhart M. Kozlosky C.J. March C.J. Black R.A. Nature. 1994; 370: 218-220Google Scholar, 39Gearing A.J. Beckett P. Christodoulou M. Churchill M. Clements J. Davidson A.H. Drummond A.H. Galloway W.A. Gilbert R. Gordon J.L. Leber T.M. Mangan M. Miller K. Nayee P. Owen K. Patel S. Thomas W. Well G. Wood L.M. Wooley K. Nature. 1994; 370: 555-557Google Scholar, 40Kojro E. Fahrenholz F. J. Biol. Chem. 1995; 270: 6476-6481Google Scholar). MT-MMPs may be responsible for the processing of many biologically important proteins on the cell surface as a regulator. These possibilities remain to be examined.In this study, we reported MT-MMP-2 as a new member of the MMP family. Since both MT-MMP-1 and −2 have TM domains at the C terminus, we proposed a new subclass for MT-MMPs in the MMP family. Studies of MT-MMPs should provide clues to understand the cell surface events controlling extracellular matrix turnover and diverse biological responses. In addition to MT-MMP-1 (MT-MMP in the previous paper), which we previously reported(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar, 2Takino T. Sato H. Yamamoto E. Seiki M. Gene (Amst.). 1995; 115: 293-298Google Scholar), we identified a new MMP gene that was expressed in a human oral malignant melanoma and a human placenta. The isolated 2.1-kilobase pair cDNA contained a sufficient coding frame for MT-MMP-2. However, the transcript in tissues or cell lines was at 12 kb in size. Since the cDNA lacks the typical polyadenylation signal (AATAAA), the 3′-non-coding region of the gene is thought to be missing in the cloned fragment. MT-MMP-1 and −2 are approximately the same in their molecular weights, but they are encoded by 4.5- and 12-kb transcripts, respectively. The most plausible explanation for the difference of the mRNA sizes is the different length of non-coding regions at their 3′-ends. MT-MMP-2 is the most closely related to MT-MMP-1 in the amino acid sequence (66% homology at the catalytic domain) and in the characteristic insertions compared to other MMPs. These insertions may be important for their function and regulation. For example, the first insertions (IS-1) between the propeptide and catalytic domain contain the conserved RXKR sequences. A similar insertion also exists in stromelysin-3 but not in others (Fig. 2B). These sequences may be the recognition site for processing, since immediately downstream of the RXKR sequences is the reported N terminus of the processed forms of stromelysin 3 and MT-MMP-1(34Murphy G. Segain J.P. O'Shea M. Cockett M. Ioannou C. Lefebvre O. Chambon P. Basset P. J Biol Chem. 1993; 268: 15435-15441Google Scholar, 35Strongin A.Y. Collier I. Bannikov G. Marmer B.L. Grant G.A. Goldberg G.I. J. Biol. Chem. 1995; 270: 5331-5338Google Scholar). Since RXKR is the consensus sequence for subtilisin-like enzymes, autocatalytic activation mechanism, which is common for other MMPs, may not be applicable for these three MMPs. Indeed, 4-aminophenylmercuric acetate or SDS that induces autocatalytic activation of pro-MMPs cannot activate stromelysin-3 and MT-MMPs. There exist 8 amino acid insertions (IS-2) in the catalytic domains of MT-MMP-1 and −2 at the same position. Three of the eight amino acids at both ends were conserved. Although the significance of this insertion is not clear, it may modulate substrate specificity of the enzymes from its position in the catalytic domain like the gelatin-binding domain of two gelatinases(36Murphy G. Nguyen Q. Cockett M.I. Atkinson S.J. Allan J.A. Knight C.G. Willenbrock F. Docherty A.J. J. Biol. Chem. 1994; 269: 6632-6636Google Scholar). Additional sequences (IS-3) containing the TM domains are found downstream of the hemopexin-like domains of MT-MMPs. Both MT-MMPs are expressed as membrane proteins embedded into the plasma membrane through the TM domains at the C terminus. Thus, these two MMPs form a unique membrane-type subclass in the MMP family, while the others are expressed as a soluble form. We previously aligned the most C-terminal portion of the cysteine residue of MT-MMP-1 to that of the hemopexin-like domain of other MMPs and thought that the TM domain is an insertion in the hemopexin-like domain(1Sato H. Takino T. Okada Y. Cao J. Shinagawa A. Yamamoto E. Seiki M. Nature. 1994; 370: 61-65Google Scholar, 2Takino T. Sato H. Yamamoto E. Seiki M. Gene (Amst.). 1995; 115: 293-298Google Scholar). However, it is more appropriate that the IS-3 locate downstream of the hemopexin-like domains of MT-MMP-1 and −2 rather than splitting the domain as shown in the alignment in Fig. 2. With this alignment, it becomes possible for MT-MMPs to form a cysteine bridge in the hemopexin-like domain, the conserved structure among the MMPs, outside of the cells. Expression of MT-MMP-2 in cells, like that of MT-MMP-1, induced activation of the pro-gelatinase A to the fully activated form (62 kDa) through the intermediate form (64 kDa). Thus, both MT-MMPs have similar biochemical activities at least in part, though it remains to be elucidated whether these MT-MMPs have different substrate specificity or not. If both MT-MMPs are similar in function, why are two separate genes required for the organism? The organism may have to utilize these MT-MMPs in different tissue environment or situations. Consistent with this idea, the tissue distribution of the MT-MMP-1 and MT-MMP-2 mRNAs was different in the human tissues. In contrast to MT-MMP-1, which is expressed widely in various tissues, MT-MMP-2 is expressed in only restricted tissues such as brain, heart, and placenta. In particular, brain tissue expresses MT-MMP-2 at the highest level but expresses MT-MMP-1 at the lowest level. The high level expression of MT-MMP-2 in brain may suggest a specific role of the product in the central nervous system. In cell lines, squamous cell carcinoma OSC-19 and human embryonal lung fibroblasts express MT-MMP-1 mRNA at higher levels but MT-MMP-2 mRNA at lower levels. The reverse was also the case; the MT-MMP-1 mRNA level was low in T24 cells where MT-MMP-2 mRNA was expressed predominantly. Since MT-MMP-2 was originally detected in oral malignant melanoma, whether MT-MMP-2 is also involved in activation of gelatinase A in tumor tissues like MT-MMP-1 is of interest. Our preliminary findings with lung carcinomas where MT-MMP-1 was overexpressed indicated that MT-MMP-2 was not expressed frequently there. 2T. Takino, H. Sato, A. Shinagawa, and M. Seiki, unpublished results. In addition to the activation of pro-gelatinase A, some of the proteins, such as β-amyloid precursor protein, tumor necrosis factor-α, and V-2 vasopressin receptor, are reported to be processed on the cell membrane by MMP-like activities(37Miyazaki K. Hasegawa M. Funahashi K. Umeda M. Nature. 1993; 362: 839-841Google Scholar, 38Mohler K.M. Sleath P.R. Fitzner J.N. Cerretti D.P. Alderson M. Kerwar S.S. Torrance D.S. Otten-Evans C. Greenstreet T. Weerawarna K. Kronheim S.R. Petersen M. Gerhart M. Kozlosky C.J. March C.J. Black R.A. Nature. 1994; 370: 218-220Google Scholar, 39Gearing A.J. Beckett P. Christodoulou M. Churchill M. Clements J. Davidson A.H. Drummond A.H. Galloway W.A. Gilbert R. Gordon J.L. Leber T.M. Mangan M. Miller K. Nayee P. Owen K. Patel S. Thomas W. Well G. Wood L.M. Wooley K. Nature. 1994; 370: 555-557Google Scholar, 40Kojro E. Fahrenholz F. J. Biol. Chem. 1995; 270: 6476-6481Google Scholar). MT-MMPs may be responsible for the processing of many biologically important proteins on the cell surface as a regulator. These possibilities remain to be examined. In this study, we reported MT-MMP-2 as a new member of the MMP family. Since both MT-MMP-1 and −2 have TM domains at the C terminus, we proposed a new subclass for MT-MMPs in the MMP family. Studies of MT-MMPs should provide clues to understand the cell surface events controlling extracellular matrix turnover and diverse biological responses. We thank Drs. Y. Okada, J. Tanaka, and M. Fujii for critical discussion and Dr. Iwata (Fuji Chemical Industries Ltd.) for cooperation to develop the monoclonal antibodies. Note added in Proof-Two new MT-MMP-2s were reported at the Gordon Research Conference on Matrix Metalloproteinases (Andover, NH July 16-21, 1995). The one reported by Will et al. (Will, B., and Hinzmann, B.(1995) Eur. J. Biochem. 231, 602-608) was published just prior to this article. Thus, we agreed to rename MT-MMP-2 in this paper as MT-MMP-3." @default.
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W2020973067 title "Identification of the Second Membrane-type Matrix Metalloproteinase (MT-MMP-2) Gene from a Human Placenta cDNA Library" @default.
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