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J. Biol. Chem., Vol. 280, Issue 1, 88-93, January 7, 2005
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Membrane-type Matrix Metalloproteinase-1 (MT1-MMP) Is a Processing Enzyme for Human Laminin 
2 Chain*
¶||
From the
Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan, The Scripps Research Institute, Department of Cell Biology, La Jolla, California 92037, and the ¶Department of Cancer Biology and Center for Matrix Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6840
Received for publication, October 18, 2004
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Processing of the laminin-5 (Ln-5)
2 chain by membrane-type-1 matrix metalloproteinases (MT1-MMP) promotes migration and invasion of epithelial and tumor cells. We previously demonstrated that MT1-MMP cleaves the rat 2 chain at two sites, producing two major C-terminal fragments of 100 (2') and 80 (2x) kDa and releasing a 30-kDa fragment containing epidermal growth factor (EGF)-like motifs (domain III (DIII) fragment). The DIII fragment bound the EGF receptor (EGF-R) and stimulated cell scattering and migration. However, it is not yet clear whether human Ln-5 is processed in a similar fashion to rat Ln-5 because one of the two MT1-MMP cleavage sites present in rat 2 is not found in human 2. To identify the exact cleavage site for MT1-MMP in human Ln-5, we purified both the whole molecule as well as a monomeric form of human 2 that is frequently expressed by malignant tumor cells. Like rat Ln-5, both the monomer of 2, as well as the 2 derived from intact Ln-5, were cleaved by MT1-MMP in vitro, generating C-terminal 2' (100 kDa) and 2x (85 kDa) fragments and releasing DIII fragments (25 and 27k Da). In addition to the conserved first cleavage site used to generate 2', two adjacent cleavage sites (Gly559–Asp560 and Gly579–Ser580) were found that could generate the 2x and DIII fragments. Two of the three EGF-like motifs present in the rat DIII fragment are present in the 27-kDa human fragment, and like the rat DIII, this fragment can promote breast carcinoma cell migration by engaging the EGF-R. These results suggest that MT1-MMP processing of Ln-5 in human tumors may stimulate the EGF-R, resulting in increased tumor cell scattering and migration that could possibly increase their metastatic potential. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Laminin-5 (Ln-5),1 a major component of the basement membrane, is a heterotrimer composed of
3, 
3, and 2 subunits (1, 2). Migration and scattering of epithelial and tumor cells are induced by proteolytic processing of the 2 chain of Ln-5. The 2 chain is a 140-kDa polypeptide and forms a triple helix with the other subunits at its C-terminal (see Fig. 1A) (3, 4). Processing of the 2 chain occurs at the N terminus generating two major C-terminal fragments of 100 (2') and 80 (2x) kDa (see Fig. 1A), and this processing has been observed in different species including humans and rodents (3, 4). Because of the limited availability of purified Ln-5, most biochemical studies in this area have been carried out using the rat protein. MT1-MMP and MMP-2 were identified as the proteases responsible for the second cleavage of the N terminus generating the 2x fragment (3, 4). In contrast, only MT1-MMP cleaved the first site to generate the 2' fragment (5). The two cleavage sites on the rat 2 chain were identified as Gly434–Asp435 for 2' and Ala586–Leu587 for 2x (3, 6).
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Processing of the rat
2 chain at these two sites releases an internal fragment containing three of the four EGF-like motifs in domain III (DIII) (7). Although Ln-5 does not stimulate the EGF receptor (EGF-R), the DIII fragment released has the ability to bind EGF-R and induce its phosphorylation (8). Inhibition of the processing using MMP inhibitors or inhibition of EGF-R activity using specific kinase inhibitors abolished cell migration on Ln-5 (8). Thus, the DIII fragment generated by this processing appears to play a major role in the observed biological effect of Ln-5 and MT1-MMP. This system seems to function in vivo as well because MT1-MMP-deficient mice showed significantly reduced processing of the 2 chain in the kidney, resulting in abnormalities terminal differentiation of the tubular epithelium (5).
Processing of the 2 chain by MT1-MMP appears to play a critical roles in tumor growth and progression because the 2 chain is frequently expressed as a monomer in malignant tumors that express MT1-MMP (9, 10). In addition, aggressive melanoma cells are known to form vascular-like networks (vascular mimicry) requiring expression of MT1-MMP and the 2 chain (11). Treatment of these cells with a neutralizing antibody against MT1-MMP or antisense oligonucleotide against the 2 gene abrogated the mimicry (11). It has also been reported that the 2' and 2x fragments in humans are similar in size to those in the rat (3, 4), suggesting that the processing of the human 2 chain by MT1-MMP is similar to that of the rat.
However, a comparison of rat and human 2 sequences reveals that although the first site (Gly434–Asp435) is conserved in humans, the second cleavage site of rat 2 (Ala586–Leu587) is not. Thus, it is not known whether MT1-MMP directly cleaves the second site in addition to the first and generates 2x and the DIII fragment. Further confusion has been raised by two contradictory reports on this issue. Veitch et al. (12) reported that the human 2 chain cannot be processed by MT1-MMP even at the first site, which is conserved between rodents and humans. Instead of MT1-MMP, they reported that the astacin family of proteases, such as bone morphogenic protein-1 (BMP-1) and mammalian Tolloid-like metalloproteinases, cleave the 2 chain (12, 13). On the other hand, Gilles et al. (14) reported that recombinant MT1-MMP induces processing of Ln-5 deposited in the extracellular matrix, although the cleavage sites were not identified, and it was not clear whether a DIII-like fragment was generated as a result of the processing.
In this manuscript, we have attempted to settle this controversy by identifying the cleavage sites on the human 2 chain cut for MT1-MMP. To this end, we purified the 2 chain either as a monomer or as a heterotrimer (Ln-5) from human cancer cell lines. Incubation of the purified 2 chain and Ln-5 with a recombinant catalytic fragment of MT1-MMP generated the two C-terminal fragments (2' and 2x) and released DIII-like fragments functionally. By purifying the 2x fragment, two adjacent cleavage sites were determined. In addition, the 2 monomeric chain that is expressed in human malignant tumors show greater sensitivity to MT1-MMP than the heterotrimer form of Ln-5.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cells and Cell Culture—MKN45, a human gastric carcinoma cell line, was provided by the Japanese Collection of Research Bioresources (Tokyo, Japan). Mum2B, a human melanoma cell line, was a gift from Professor Mary Hendrix, University of Iowa, Iowa City, IA. STKM-1, a human gastric carcinoma cell line, was obtained from Dr. Shunsuke Yanoma, Kanagawa Cancer Center, Research Institute, Yokohama, Japan. All cell lines were cultured at 37 °C in a humidified atmosphere of 5% CO2, 95% air. Dulbecco's modified Eagle's medium or RPMI 1640 medium (Sigma) supplemented with 10 mM HEPES, 1.2 mg/ml of NaHCO3, and 2 mM glutamate was used as basal medium and supplemented with 10% fetal bovine serum (Irvine Scientific, Irvine, CA).
SDS-PAGE and Western Blotting—The method for SDS-PAGE was described in our previous report (4). The Western blotting was performed as reported (4). Serum-free conditioned medium was collected from confluent cultures of cancer cells incubated for 2 days in serum-free medium. The serum-free conditioned medium was concentrated about 30-fold with ammonium sulfate at 80% saturation as described in our previous report (4). The cell lysate was prepared with 20 mM Tris-HCl, 1% Triton X-100, 0.005% Brij-35. The protein concentration was measured with a Bio-Rad dye binding kit using bovine serum albumin as a standard.
Purification of Human Laminin-5 and Laminin 2 Monomer—Human Ln-5 and the laminin 2 monomer (Ln 2) were purified using anti-human Ln 2 monoclonal antibody (D4B5)-conjugated immunoaffinity chromatography from serum-free conditioned medium of the STKM-1 and Mum2B cell lines, respectively. The purification procedure and other experimental conditions were reported previously (4).
N-terminal Sequencing—Automated N-terminal amino acid sequencing was performed with an Applied Biosystems model 419A protein sequencer (15).
Cleavage of Ln-5 2 and Monomeric Ln 2 by MT1-MMP in Vitro— Purified Ln-5 (1.5 µg) or Ln 2 (0.5 µg) was digested with recombinant MT1-MMP at a given concentration for 18 h at 37 °C in 50 mM Tris (pH 7.5), 0.005% Brij-35, 0.1% CHAPS, and 10 mM CaCl2, electrophoresed with a 4–20% gradient on SDS-PAGE gel under reducing conditions, and analyzed by Western blotting with a polyclonal antibody against domain III of Ln 2 (2778). The methods and conditions are described in previous reports (4).
Transfection of MT1-MMP Expression Vector into Cancer Cells— Transfection with the pSG-MT1-MMP vector (1 µg/5 x 105 cells seeded in each well of 6-well plates) was done with the FuGeneTM 6 reagent as recommended. After 2 days of transfection, the conditioned medium and cellular lysate were collected and analyzed by Western blotting for Ln 2 and its proteolytic fragments. The transfection procedure and experimental conditions were reported elsewhere (16).
Expression and Purification of Human Recombinant DIII (rDIII) Fragment—Total RNA from STKM-1 (human gastric carcinoma cell line) was subjected to reverse transcription-PCR, and a gene encoding human Ln 2 chain was obtained. A gene fragment (435 bp) corresponding to the coding region for Asp435–Gly579 was then amplified by PCR, fused with a FLAG coding sequence at the 3' end, and subcloned into the pCDNA 3.1 (+) mammalian expression vector (Invitrogen). The expression plasmid was transfected into COS-7 cells, and the recombinant rDIII protein was expressed as a secreted form. rDIII protein that accumulated in the serum-free conditioned medium was purified by two series of column chromatography, an affinity column conjugated with anti-FLAG mAb (M2) and an anion-exchange HPLC on a QAE-825 column. The purified rDIII fragment was confirmed by SDS-PAGE and Western blotting.
Transwell Migration Assay—Cell migration assays were performed using Transwell chambers as described in our previous report (5). Briefly, the filter undersides were coated with human Ln-5 (500 ng/ml) overnight at 4 °C, blocked with 5% milk, phosphate-buffered saline, 0.05% Tween 20 for 2 h at room temperature, washed with phosphate-buffered saline twice, and used for cell migration assays. MDA-MB-231 cells were resuspended in Dulbecco's modified Eagle's medium and 0.1% bovine serum albumin in the absence or presence of human rDIII protein (1.3 µM) and were seeded into the upper chamber at 20,000 cells/Transwell chamber. After an 8-h incubation with/without an anti-human EGF-R neutralizing antibody (10 µg/ml) (LA-1) (Upstate Group, Inc, Charlottesville, VA), cells on the upper filter were scrapped and washed with phosphate-buffered saline three times, and then migrating cells on the lower filter were fixed with 100% MeOH and stained with 0.25% crystal violet, 20% MeOH for 15 and 30 min, respectively. Each bar represents the mean ± S.D. for cell migration in three wells.
Reagents—Monoclonal antibody to human -actin and polyclonal antibody to human BMP-1 were purchased from Chemicon International Inc. (Temecura, CA). Immobilon membranes were from Millipore (Bedford, MA). The transmigration chamber was from Corning-Corster (Corning, NY). Transmembrane domain-deleted recombinant MT1-MMP, polyclonal antibody against rat Ln 2 (2778), and monoclonal antibody to MT1-MMP were produced by our laboratories (3, 17, 18).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Purification of Human Laminin-5 and Laminin
2 Monomer—The human cancer cell lines Mum2B and STKM-1 express the 2 chain as both a monomer and a heterotrimer, Ln-5, respectively. Serum-free conditioned medium of the cells was used to purify both forms of the 2 chain using an immunoaffinity column conjugated with a monoclonal antibody (D4B5) against the DIII domain of rat 2. The purified preparation from Mum2B cells contained one major (140 kDa) and two minor (280 and 100 kDa) polypeptides as detected by silver staining in Fig. 1B. Based on previous studies, the 140-kDa protein corresponded to the intact 2 chain, and the 280-kDa protein is presumably a dimer. The smaller band (100 kDa) corresponded to 2' cleaved at the first site, and the very weak band (85 kDa) corresponded to 2x cleaved at the second site (Fig. 1, A and B). On the other hand, the preparation from STKM-1 cells contained 3 (160-kDa) and 3 (135-kDa) chains in addition to 2 (140 and 100 kDa). However, most of the 2 chain was detected as 2', and the amount of intact 2 chain was negligible (Fig. 1B). A very faint band corresponding to 2x was also detected.
Processing of Human Ln 2 Chain by MT1-MMP—The Ln 2 chain and 2' fragment were also detected by Western blotting using a polyclonal antibody against the rat DIII domain (Fig. 2, A and B). A fully processed 2x fragment was weakly detectable by the antibody, although the amount of DIII fragment was negligible in these preparations (Fig. 2, see MT1-MMP 0 nM). The results presumably indicate that the mAb D4B5 used for the preparation recognizes the C-terminal part of the DIII domain, and this portion is not included in the clipped DIII fragment as illustrated in Fig. 2C. To examine whether MT1-MMP cleaves 2 and 2', purified protein samples were incubated with increasing amounts of a catalytic fragment of human MT1-MMP. The amount of 2 monomer decreased and that of 2x and the DIII fragment increased dependent on the concentration of MT1-MMP (Fig. 2A, from 4 to 20 nM). Thus, the human Ln 2 chain can be cleaved by MT1-MMP like its rat counterpart. The amount of 2' did not change significantly presumably because of the balance between production and further processing. The 2 chain in Ln-5 was also processed into 2x by MT1-MMP, and the DIII fragment was generated (Fig. 2B). However, it is of note that the processing of the 2 chain in Ln-5 requires 10 times more MT1-MMP than the processing of the single chain form. Thus, the two forms of the 2 chain differ in their susceptibility to MT1-MMP.
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Since the first cleavage site identified for the rat
2 chain is conserved, along with its flanking sequences, in humans (Fig. 2C), it is most likely that cleavage to generate the 2' fragment occurs at this site. Thus, we tried to identify the second cleavage site that generates 2x. The 2x fragment was extracted from the polyacrylamide gel and sequenced. Two N-terminal sequences were identified in the 2x preparation, Asp-Pro-Leu-Ala and Ser-Glu-Pro-Val. Thus, the two cleavage sites were identified as Gly559–Asp560 and Gly579–Ser580 (Fig. 2C). Although the Gly559–Asp560 sequence is not conserved in rats, Gly579–Ser580 is present in its flanking sequences (Fig. 2C), which, although unreported, may be a cleavage site for the rat 2 chain.
The human DIII fragments are calculated to be 152 and 145 amino acids long, respectively, and presumably correspond to the 27- and 25-kDa bands in Fig. 2, A and B. Thus, human 2 fragments are generated by MT1-MMP as in rodents.
Human DIII Fragment Stimulates Carcinoma Cell Migration—We previously described that the rat DIII fragment contained three EGF-like motifs and promoted cell migration by engaging the EGF-R (8). As the human DIII fragment only contained two of the three motifs (Figs. 1A and 2C), we attempted to confirm whether the human DIII fragment (Asp435–Gly579) retained its activity to stimulate EGF-R. To do this, we expressed a secreted form of the recombinant rDIII protein with a FLAG tag at the C terminus in COS-7 cells. The rDIII fragment was purified from the serum-free conditioned medium using anti-FLAG antibody and subsequently by an anion-exchange HPLC. The final preparation contained a 27-kDa single protein band as detected by silver staining after SDS-PAGE (Fig. 3A, left), and the band reacted with anti-FLAG M2 antibody (Fig. 3A, right).
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The effect of the rDIII on migration of MDA-MB-231 cells was analyzed using a Transwell chamber. Addition of human rDIII (1.3 µM) resulted in a 1.5-fold increase in migration on Ln-5 (Fig, 3B) and this effect was completely abolished by a neutralizing antibody against EGF-R, LA-1. Thus, the two EGF-like motifs retained in the human DIII fragment appear to be sufficient to induce EGF-R-dependent cell migration.
Cell-mediated Processing of the Human Ln 2 Chain by MT1-MMP—To examine whether MT1-MMP is responsible for cell-mediated processing of the human 2 chain, MT1-MMP was transiently expressed into Mum2B cells, and conditioned media was analyzed by Western blotting (Fig. 4A). Untransfected Mum2B cells express MT1-MMP at a low level and constitutively release C-terminal fragments of 2 as well. Forced expression of MT1-MMP increased the amount of 2' and 2x fragments. To confirm that the 2 chain of in Ln-5 is processed from the intact Ln-5 molecule by MT1-MMP in a cell-mediated manner, we used human gastric carcinoma MKN45 cells. MKN45 cells produce Ln-5 containing only an intact form of the 2 chain (Fig. 4B), and they do not express endogenous MT1-MMP at detectable levels as expected from the low levels of 2 processing. Expression of MT1-MMP in the cells resulted in a significant amount of the 2' fragment, although little 2x was detected at least under these conditions (Fig. 4A). The processing was inhibited by 10 µM MMP inhibitor BB94 (data not shown). Thus, the cell-associated form of MT1-MMP promotes the processing of both forms of the human 2 chain.
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To determine whether there was a correlation between the expression levels of processing enzymes and Ln-5 processing, we assessed whether there was a correlation between endogenous MT1-MMP and the amount of cleavage observed. Ln-5 produced by STKM-1 cells and Ln-5 produced by Mum2B cells were both found in the cleaved form, and the Ln-5 in the STKM-1 cells contained only a small amount of intact
2 chain, whereas most of the 2 chains were detected as processed forms (Fig. 1B). All three cell lines were analyzed by Western blotting with an antibody to MT1-MMP. MT1-MMP was detected in Mum2B cells but not in STKM-1 or MKN45 cells (Fig. 4C). As BMP-1 has also been reported as a potential processing enzyme for Ln-5 (13), we determined whether it was found in the cells. STKM-1 (Fig. 4C) cells were the only line to express this enzyme. Thus, BMP-1 appears to be responsible for the processing by the cells, and MT1-MMP appears to be responsible for that by Mum2B cells. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This study was performed due to the debate over the ability of MT1-MMP to cleave the human Ln
2 chain. We demonstrated that when monomeric or Ln-5 forms of the human 2 chain were purified and incubated with MT1-MMP, two major C-terminal fragments, 2' and 2x, were formed as reported for rat Ln-5. The first cleavage, which generates 2', presumably occurs at the same site as rat 2 because the cutting site, including flanking sequences, is well conserved between the two species. At the location of the second cleavage sites, which generates the 2x fragment, we identified two adjacent sites (Gly559–Asp560 and Gly579–Ser580). Since the sites are close together, the two 2x bands could not be separated clearly by SDS-PAGE (Fig. 2, A and B). This cleavage at the two different sites resulted in the formation of two DIII fragments (25 and 27 kDa) by MT1-MMP.
The Ln 2 chain is frequently expressed in malignant human tumors. Using the human cell line Mum2B, we purified a monomeric form of 2 and compared the processing of the monomer by MT1-MMP with that of Ln-5. Interestingly, the monomer was 10 times more sensitive to MT1-MMP than the Ln-5 form. Since the 2 monomer is frequently expressed together with MT1-MMP in malignant tumors, a similar processing of the 2 chain may be occurring in tumors. This result supports the previous observations that both 2 and MT1-MMP were required for melanoma cells to show vascular mimicry (11). We have also found that rat Ln-5 showed greater sensitivity to MT1-MMP than human Ln-5 (data not shown). The relatively resistant nature of human Ln-5 may be why Veitch et al. (12) could not detect its processing by MT1-MMP. It is not clear whether the difference in sensitivity affects the biological outcome mediated by Ln-5 and MT1-MMP in humans significantly.
The second cleavage site, which generates the rat 2x fragment, is not conserved in humans (3, 6), and two new cleavage sites were identified for human 2x. Although one site (Gly559–Asp560) is not conserved in the rat sequence, the other site (Gly579–Ser580) is. Thus, in addition to the rat 2x site (Ala586–Leu587) reported previously, the conserved second site (Gly558–Ser559) in rat Ln 2 may also be cleaved by MT1-MMP. Cleavage at the first and second sites in human Ln 2 generates shorter DIII fragments than in the rat (7 and 27 amino acids, respectively). Although the 27-kDa human DIII fragment retains only two of the three EGF-like motifs present in the in rat DIII fragment (7, 8), it induced EGF-R-dependent carcinoma cell migration (Fig. 3B). Thus, the human DIII fragment appears to function as an EGF-R ligand.
We also examined the expression of MT1-MMP and BMP-1 in three human tumor cell lines that produce 2 as either an intact or a processed form. Mum2B cells expressed MT1-MMP and produced processed forms of 2. STKM-1 cells produced Ln-5 containing processed forms of the 2 fragments and expressed BMP-1, another candidate for a protease that processes human Ln-5 (5, 12, 13) but not MT1-MMP. MKN45 cells that produce Ln 2 as an intact form expressed neither MT1-MMP nor BMP-1. Enforced expression of MT1-MMP in MKN45 cells induced cell-mediated processing of the 2 chain in Ln-5. Thus, multiple proteases including MT1-MMP and BMP-1 appear to mediate processing of the 2 chain, and the proteases responsible for the processing may differ depending on cell type and tissue. For example, although the processing of Ln 2 in kidney and lung is significantly reduced in MT1-MMP-deficient mice (5), such a reduction was not evident in other organs. On the other hand, mice lacking both BMP-1 and mammalian Tolloid-like metalloproteinases show reduced processing of Ln 2, particularly in skin (12), although it is not clear whether this occurs in other tissues as well.
In conclusion, human Ln 2 is processed by MT1-MMP and generates DIII fragments containing at least two EGF-like motifs. Moreover, recombinant DIII fragment significantly increases cancer cell migration activity by engaging EGF-R. The monomeric form is 10 times more sensitive to MT1-MMP than the 2 chain in Ln-5. Thus, MT1-MMP can act as a processing enzyme for both human and rat 2 and presumably promotes cell migration and invasion through the action of the released DIII fragment (8).
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FOOTNOTES |
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* This work was supported by National Institutes of Health Grants GM46902 and CA47858 (to V. Q) and by the Special Coordination Fund for promoting science and a grant-in-aid for cancer research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to M. S and N. K). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|| To whom correspondence should be addressed. Fax: 81-3-5449-5414; E-mail: mseiki{at}ims.u-tokyo.ac.jp.
1 The abbreviations used are: Ln-5, laminin-5; Ln 2, laminin 2; MT-MMP, membrane-type matrix metalloproteinase; BMP-1, bone morphogenic protein-1; EGF, epidermal growth factor; EGF-R, EGF receptor; BM, basement membrane; DIII, domain III; rDIII, recombinant DIII; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; mAb, monoclonal antibody; HPLC, high pressure liquid chromatography..
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ACKNOWLEDGMENTS |
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We acknowledge Dr. Roy Zent for critical reading of this manuscript.
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 N. Koshikawa, T. Minegishi, K. Nabeshima, and M. Seiki Development of a New Tracking Tool for the Human Monomeric Laminin-{gamma}2 Chain In vitro and In vivo Cancer Res., January 15, 2008; 68(2): 530 - 536. [Abstract] [Full Text] [PDF]
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 F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]
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 J. J. Atkinson, H. M. Toennies, K. Holmbeck, and R. M. Senior Membrane type 1 matrix metalloproteinase is necessary for distal airway epithelial repair and keratinocyte growth factor receptor expression after acute injury Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L600 - L610. [Abstract] [Full Text] [PDF]
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 S. Langlois, C. Nyalendo, G. Di Tomasso, L. Labrecque, C. Roghi, G. Murphy, D. Gingras, and R. Beliveau Membrane-Type 1 Matrix Metalloproteinase Stimulates Cell Migration through Epidermal Growth Factor Receptor Transactivation Mol. Cancer Res., June 1, 2007; 5(6): 569 - 583. [Abstract] [Full Text] [PDF]
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C. Nyalendo, M. Michaud, E. Beaulieu, C. Roghi, G. Murphy, D. Gingras, and R. Beliveau Src-dependent Phosphorylation of Membrane Type I Matrix Metalloproteinase on Cytoplasmic Tyrosine 573: ROLE IN ENDOTHELIAL AND TUMOR CELL MIGRATION J. Biol. Chem., May 25, 2007; 282(21): 15690 - 15699. [Abstract] [Full Text] [PDF]
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A. P. Petty, K. L. Garman, V. D. Winn, C. M. Spidel, and J. S. Lindsey Overexpression of Carcinoma and Embryonic Cytotrophoblast Cell-Specific Mig-7 Induces Invasion and Vessel-Like Structure Formation Am. J. Pathol., May 1, 2007; 170(5): 1763 - 1780. [Abstract] [Full Text] [PDF]
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 K. Sugawara, D. Tsuruta, H. Kobayashi, K. Ikeda, S. B. Hopkinson, J. C.R. Jones, and M. Ishii Spatial and Temporal Control of Laminin-332 (5) and -511 (10) Expression During Induction of Anagen Hair Growth J. Histochem. Cytochem., January 1, 2007; 55(1): 43 - 55. [Abstract] [Full Text] [PDF]
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K. J. Greenlee, Z. Werb, and F. Kheradmand Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted Physiol Rev, January 1, 2007; 87(1): 69 - 98. [Abstract] [Full Text] [PDF]
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D. Joly, S. Berissi, A. Bertrand, L. Strehl, N. Patey, and B. Knebelmann Laminin 5 Regulates Polycystic Kidney Cell Proliferation and Cyst Formation J. Biol. Chem., September 29, 2006; 281(39): 29181 - 29189. [Abstract] [Full Text] [PDF]
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 B. Kim, H. Koo, S. Yang, S. Bang, Y. Jung, Y. Kim, J. Kim, J. Park, R. T. Moon, K. Song, et al. TC1(C8orf4) Correlates with Wnt/{beta}-Catenin Target Genes and Aggressive Biological Behavior in Gastric Cancer. Clin. Cancer Res., June 1, 2006; 12(11): 3541 - 3548. [Abstract] [Full Text] [PDF]
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N. Oku, E. Sasabe, E. Ueta, T. Yamamoto, and T. Osaki Tight Junction Protein Claudin-1 Enhances the Invasive Activity of Oral Squamous Cell Carcinoma Cells by Promoting Cleavage of Laminin-5 {gamma}2 Chain via Matrix Metalloproteinase (MMP)-2 and Membrane-Type MMP-1. Cancer Res., May 15, 2006; 66(10): 5251 - 5257. [Abstract] [Full Text] [PDF]
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 A. G. Remacle, D. V. Rozanov, P. C. Baciu, A. V. Chekanov, V. S. Golubkov, and A. Y. Strongin The transmembrane domain is essential for the microtubular trafficking of membrane type-1 matrix metalloproteinase (MT1-MMP) J. Cell Sci., November 1, 2005; 118(21): 4975 - 4984. [Abstract] [Full Text] [PDF]
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