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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.]
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ABSTRACT |
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Introduction |
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In recent years, the number of known members of the MMP family has grown rapidly, mainly due to the discovery of a series of membrane-bound enzymes belonging to the MT-MMP subfamily (3, 4, 5, 6, 7) . To date, this MMP subfamily is composed of five members that are structurally characterized by having a hydrophobic region downstream of the hemopexin-like domain present in most MMPs. MT-MMPs have raised additional interest for their role as cell surface activators of progelatinase A, an enzyme widely assumed to play an important role in the invasive phenotype of tumor cells (2) . Progelatinase A activation by MT-MMPs involves a two-step mechanism, analogous to that operating in other MMPs. The initial cleavage is mediated by direct action of MT-MMPs in a region of the progelatinase A propeptide domain that is exposed to solvent, whereas the secondary cleavage is autoproteolytic. This activation process appears to involve the formation of a trimolecular complex between proge-latinase A, MT1-MMP, and tissue inhibitor of metalloproteinase 2 that acts as a concentration mechanism on the cell surface that is crucial for the efficiency of activation (8) . More recently, MT-MMPs have been reported to participate in the activation of other MMPs such as procollagenase 3 that are also associated with a number of human malignant tumors (9, 10, 11) . Moreover, these membrane proteases have the ability to directly degrade a variety of extracellular matrix proteins such as vitronectin, fibronectin, fibrillar collagens, or aggrecan (12) and to regulate neovascularization processes by acting as pericellular fibrinolysins (13) . Finally, it has been described that MT1-MMP enables invasive migration of glioma cells due to its ability to digest central nervous system myelin-inhibitory proteins (14) .
Because of the importance of MT-MMPs in both normal and tumor processes, we have undertaken studies to try to identify novel members of this family produced by human tissues. In this study, we describe the isolation of a cDNA coding for a novel human MT-MMP that has been called MT6-MMP. We also perform an analysis of its potential role as a progelatinase A activator at the cell surface. Finally, we report an expression analysis of MT6-MMP in normal and tumor tissues, including a comparative study of the expression of this novel enzyme and other MT-MMPs in brain tumors.
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Materials and Methods |
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gt10 and Northern blots containing
poly(A)+ RNAs from different human tissues and cell lines
were obtained from Clontech (Palo Alto, CA).
Screening of a Human Fetal Liver cDNA Library.
A computer search of the different human DNA sequence databases for
entries with similarity to previously described MMPs led us to find a
genomic sequence identified by Bernot et al.
(15)
in the course of their studies directed at cloning
the gene responsible for the inherited disease called FMF. To isolate a
full-length cDNA corresponding to the putative MMP identified by Bernot
et al. (15)
, we first performed PCR
amplification of DNAs prepared from cDNA libraries available in our
laboratory, using two primers (5'-TACGCTCTGAGCGGCAGCGTG-3' and
5'-CTCATCGTCAAAGTGAGTGTCC-3') derived from the genomic sequence. The
PCR reaction was carried out in a GeneAmp 2400 PCR system from
Perkin-Elmer/Cetus (Norwalk, CT) for 35 cycles of denaturation (94°C,
15 s), annealing (62°C, 15 s), and extension (72°C,
15 s). A DNA fragment of 315 bp was amplified from human fetal
liver cDNA. This PCR-generated product was phosphorylated with T4
polynucleotide kinase and cloned into a EcoRV-cut
pBluescript vector. The cloned cDNA was then excised from the vector,
radiolabeled, and used to screen a human fetal liver cDNA library
according to standard procedures. After plaque purification, the cloned
inserts were excised by EcoRI digestion, and the resulting
fragments were subcloned into pBluescript.
Nucleotide Sequence Analysis.
DNA fragments of interest were cloned into pBluescript and sequenced by
the dideoxy chain termination method using the Sequenase Version 2.0
kit (United States Biochemicals, Cleveland, OH). All nucleotides were
identified in both strands. Computer analysis of DNA and protein
sequences was performed with the Genetics Computer Group
software package of the University of Wisconsin Genetics
Computer Group.
Northern Blot Analysis.
Nylon filters containing 2 µg of poly (A)+ RNA of human
tissues or tumor cell lines or 10 µg of total RNA from brain tumors
were prehybridized at 42°C for 3 h in 50% formamide, 5x SSPE
[1x SSPE = 150 mM NaCl, 10 mM
NaH2PO4, and 1 mM EDTA (pH 7.4)],
10x Denhardt’s solution, 2% SDS, and 100 µg/ml denatured herring
sperm DNA and then hybridized for 20 h under the same conditions
with a probe specific for MT6-MMP. Filters were washed with 0.1x SSC,
0.1% SDS for 2 h at 50°C and exposed to autoradiography. RNA
integrity and equal loading were assessed by hybridization with actin
or 18S RNA probes.
Gelatin Zymography.
Samples were mixed with SDS sample buffer in the absence of a reducing
agent and subjected to electrophoresis without boiling on 10%
acrylamide gels containing 0.2% gelatin. Gels were run at 10 mA,
washed in 2.5% Triton X-100 for 3 h, and incubated at 37°C for
20 h in reaction buffer [20 mM Tris-HCl (pH 7.4), 5
mM CaCl2]. After incubation, gels were stained
with Coomassie Brilliant Blue R-250. The gelatinolytic activities were
detected as clear bands in the blue background.
Construction of Eukaryotic Expression Vectors, Cell Transfection,
and Immunolocalization.
A modified MT6-MMP cDNA encoding an open reading frame comprising amino
acids Met1-Arg562 and containing an internal
24-bp sequence coding for the HA epitope of human influenza virus was
generated by PCR and cloned in the EcoRV site of a pcDNA3
vector. Thus, the resulting MT6-MMP protein was HA-tagged between the
hemopexin domain and the COOH-terminal extension rich in hydrophobic
residues present in this protein. Expression plasmids for progelatinase
A were kindly provided by Drs. G. Murphy and V. Knäuper
(University of East Anglia, Norwich, United Kingdom). COS-7 cells were
transfected with 1 µg of plasmid DNA, using Lipofectamine reagent
(Life Technologies, Inc.) according to the manufacturer’s
instructions. Forty-eight h after transfection, cells were fixed for 10
min in cold 4% paraformaldehyde in PBS, washed in PBS, and incubated
for 10 min in 0.2% Triton X-100 in PBS. Fluorescence detection was
performed by incubating the slides with monoclonal antibody 12CA5
(Boehringer Mannheim) against HA (diluted 1:2500), followed by
another incubation with goat antimouse fluoresceinated antibody
(diluted 1:50). After washing in PBS, slides were mounted with
vectashield (Vector, Burlingame, CA) and observed using a BioRad
confocal laser microscope. COS-7 extracts were also obtained for
Western blot analysis of the MT6-MMP-HA protein.
Western Blot Analysis.
COS-7 cells were transiently transfected with the pcDNA3 MT6-MMP-HA
plasmid as described previously. Cells were rinsed in PBS and
scraped from the plates. Membrane fractions were prepared essentially
following the procedure described by Zucker et al.
(16)
. Extracts were separated by SDS-PAGE, analyzed by
Western blotting with an anti-HA monoclonal antibody, and detected with
an enhanced chemiluminescence kit (Amersham).
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Results |
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-phage DNA obtained from a human fetal liver cDNA library. The
PCR-amplified product was cloned, and its identity was confirmed by
nucleotide sequencing. The cloned fragment was then radiolabeled and
used as a probe to screen the same fetal liver cDNA library used for
the previous PCR amplification experiment. Upon screening of
approximately 1 x 106 plaque-forming units,
two positive clones named 1.3.5 and 3.10.2 were identified and
characterized. DNA was isolated from these positive clones, and their
nucleotide sequence was determined by standard procedures. This
sequence analysis revealed that one of these clones (3.10.2) had an
insert of 1 kb, which was entirely contained in the 3-kb coding
sequence determined for clone 1.3.5. A detailed analysis comparing the
sequence obtained for the largest clone with those corresponding to
other MMPs suggested that it contained the entire coding sequence for
an archetypical MMP. Computer analysis of the obtained sequence
(European Molecular Biology Laboratory accession number AJ 239053; Fig. 1
) revealed an open reading frame coding for a protein of 562 amino acids
with a predicted molecular mass of 63 kDa.
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and those determined for other human MMPs
showed that the maximum percentage of identities (48%) was found with
MT4-MMP. In addition, the deduced amino acid sequence from the human
cDNA isolated in this work displays a number of structural features
characteristic of MMPs. Thus, it contains a stretch of hydrophobic
amino acids close to the initial methionine that likely corresponds to
the signal peptide that targets these proteinases to the secretory
pathway. Computer analysis using the algorithm developed by Nielsen
et al. (17)
revealed that the
Ala21-Pro22 peptide bond in the sequence
Arg-Ala-Pro-Lys presented the highest probability to be the processing
site of the leader sequence found in this MMP. Assuming that the signal
peptidase cleaves at this position, the resulting protein would be
composed of 541 residues. The multiple alignment of this sequence with
those determined for other MMPs also allows us to identify a prodomain
region with the Cys residue (at position 90) essential for maintaining
the latency of these enzymes, a catalytic domain of about 170 residues
including the consensus sequence
HEXGHXXGXXHS involved in zinc binding,
and a fragment of approximately 200 amino acids with sequence
similarity to hemopexin. In addition, this novel sequence contains a
10-amino acid insertion located between the propeptide and catalytic
domains that ends in a stretch of basic amino acid residues. This
insertion is present in all MT-MMPs and has been proposed to mediate
intracellular activation of these proteinases by furin-like enzymes.
Finally, the identified sequence contains a COOH-terminal extension
rich in hydrophobic residues that could correspond to the transmembrane
domain present in the different MT-MMPs characterized to date.
According to these structural features, we suggest that the isolated
fetal liver cDNA codes for a novel human MT-MMP that we propose calling
MT6-MMP. Nevertheless, this protein presents a structural peculiarity
shared with MT4-MMP, consistent in the absence of the short cytoplasmic
tail present in the remaining MT-MMPs. This fact, together with the
above-mentioned data indicating that the highest percentage of MT6-MMP
amino acid sequence identities was found with MT4-MMP, suggests that
both proteins may form a subgroup within the MT-MMP group of membrane
metalloproteases. On the other hand, following the nomenclature system
proposed for vertebrate MMPs, we would assign number 25 to this novel
MT-MMP, because MMP-24 corresponds to MT5-MMP (3)
. It
should be noted that although Bernot et al.
(15)
assigned number 20 to the putative MMP derived from
the genomic sequence identified by them, this number had been
previously used to designate enamelysin, a MMP family member produced
by odontoblastic cells (18)
. The discovery of some
differences between the cDNA sequence identified herein and data
derived from genomic clones is also remarkable (15)
. These
differences were likely due to errors in the sequence of genomic clones
because cDNA sequences reported in this study were confirmed in a
number of clones from different sources. We also observed that some of
these differences were located at the region coding for the
COOH-terminal extension characteristic of MT-MMPs and originated a
series of open reading frame changes that hampered the identification
of the encoded MMP as a member of the MT-MMP subfamily on the basis of
data derived from the available genomic sequences.
MT6-MMP Localization at the Cell Surface.
To provide additional support for the subcellular distribution of
MT6-MMP, COS-7 cells were transfected with pcDNA3 MT6-MMP-HA, a
construct containing the HA epitope at the end of the hemopexin domain
of MT6-MMP. Transfected cells were then analyzed by immunofluorescence
with a mouse monoclonal antibody (12CA5) specific for this viral
epitope. As shown in Fig. 2A
, a fluorescence pattern surrounding the cell was visualized in a serial
optical section obtained by the confocal microscope. This observation
provides strong evidence that human MT6-MMP is a membrane-bound MMP,
meeting the requirement for an activator of progelatinase A at the cell
surface. To further verify the membrane localization of MT6-MMP, cell
lysates from COS-7 cells transfected with MT6-MMP-HA were analyzed by
SDS-PAGE, followed by Western blotting detection with anti-HA
monoclonal antibody. A band of about 63 kDa corresponding to MT6-MMP
was detected in the membrane enriched fractions, but not in the
cytoplasmic fraction or in the conditioned medium, reinforcing its
membrane-bound localization (Fig. 2B
; data not shown).
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,Lanes 1 and 2). As shown in Fig. 3
, Lane
5, cotransfection of both cDNAs resulted in activation of
progelatinase A secreted by COS-7 cells, as assessed by the appearance
of a 62-kDa band corresponding to the activated form of this enzyme. In
contrast, transfection of the expression plasmid for progelatinase A
alone did not result in the activation of the proenzyme (Fig. 3
,
Lane 4). It is noteworthy that when an expression plasmid
for MT1-MMP was cotransfected with progelatinase A cDNA, the activation
rate of progelatinase A secreted by COS-7 cells was significatively
higher than that observed after cotransfection of MT6-MMP cDNA (Fig. 3
,
Lanes 5 and 7). Taken together, these functional
analyses suggest that the cloned human fetal liver cDNA for MT6-MMP
encodes an archetypical MT-MMP with the ability to mediate the
activation of progelatinase A. Nevertheless, the relatively low
efficiency of MT6-MMP in this activation process when compared to
MT1-MMP suggests that this novel membrane protease may also participate
in the cell surface activation of other substrates. Preliminary studies
have shown that MT6-MMP has no significant effect on the shedding of
HER2, pro-transforming growth factor-
, or heparin-binding
EGF-like growth factor (data not shown). Additional studies will
be required to identify the nature of putative substrates other than
pro-gelatinase A that could be target of the proteolytic activity
of this novel membrane-bound enzyme.
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, a transcript of about 4 kb was predominantly detected in leukocytes,
lung, and spleen. A second transcript of about 6 kb was also clearly
detected in leukocytes and spleen. Interestingly, when a full-length
probe was used, a transcript of about 1.5 kb was detected in the heart
as well as in other human tissues including the colon, intestine,
ovary, and prostate (data not shown). This mRNA transcript likely
corresponds to a second transcriptional unit identified by Bernot
et al. (15)
in this region of the human genome
that overlaps with that of MT6-MMP. This additional transcriptional
unit derives from the strand opposite to that encoding MT6-MMP and
contains stop codons in all three frames (15)
. We also
examined the possibility that MT6-MMP could be expressed by human
cancer cells from different sources, as already shown for other MMPs.
To this purpose, we hybridized a Northern blot containing
poly(A)+ RNAs extracted from different cancer cell lines
with the same MT6-MMP probe as described above. As shown in Fig. 4
, the
4-kb MT6-MMP transcript was clearly identified in colorectal
adenocarcinoma SW480 cells. Reverse transcription-PCR analysis also
revealed the expression of MT6-MMP transcripts in some primary colon
carcinomas, but not in the adjacent normal mucosa (data not shown).
Finally, we examined the possibility that MT6-MMP could be
overexpressed in brain tumors as described for other members of the
family (3
, 19)
. As can be seen in Fig. 5
, MT6-MMP transcripts were detected in some anaplastic astrocytomas and
glioblastomas, but not in normal brain or in meningiomas.
Interestingly, when the same filter was hybridized with probes specific
for other MT-MMPs, including MT1-MMP, MT4-MMP, and MT5-MMP, different
patterns of expression were observed, with MT1-MMP being more
restricted in its tumor expression than other MT-MMPs (Fig. 5)
. These
results suggest that overexpression of some of the diverse members of
the MT-MMP family by brain tumors may be a general strategy for the
cell surface focusing of degradative processes presumably linked to the
progression of these tumors.
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Discussion |
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In this study, we have also shown that MT6-MMP is a functionally active
member of this group of cell surface MMPs, as assessed by evaluating
its ability to act as a progelatinase A activator, which is a
characteristic feature of MT-MMPs. Thus, cotransfection of
expression plasmids encoding MT6-MMP and progelatinase A resulted in
activation of COS-7-secreted progelatinase A, as demonstrated by
gelatin zymography. In contrast, we did not detect any significant
effect of MT6-MMP on the ectodomain shedding of a variety of
transmembrane proteins including pro-transforming growth factor ,
HER2, and pro-heparin-binding EGF-like growth factor.
Furthermore, and in marked contrast with all of these biochemical
properties of MT6-MMP that unequivocally include this protease within
the MT-MMP subfamily, chromosomal mapping and expression analysis of
the MT6-MMP gene (MMP-25) have revealed a series of features
that are unique to this novel family member. Thus, the localization of
genomic sequences for MT6-MMP in the region immediately close to the
FMF gene (15)
demonstrates that MMP26 is
located at chromosome 16p13.3, a unique position among all known MT-MMP
genes, which have been localized to chromosomes 14q11 (MT1-MMP), 16q13
(MT2-MMP), 8q21 (MT3-MMP), 12q24 (MT4-MMP), and 20q11.2 (MT5-MMP; Refs. 3
, 20
, and 21
). This situation contrasts with the case of the MMPs
located at the 11q22 cluster, which contains at least eight different
family members tightly linked in a small region of the human genome
(18
, 22)
. Therefore, transposition events within
subfamilies have contributed to a higher diversification of this gene
family, likely reflecting a strong selective pressure on the
requirements to degrade distinct protein components of connective
tissues or as an adaptation to cleave similar substrates in different
tissues. Consistent with this proposal, the pattern of MT6-MMP
expression in human tissues is completely different from those reported
for the remaining MT-MMPs. Thus, in this study, we have shown that this
gene is predominantly expressed in leukocytes, lung, and spleen. None
of the remaining MT-MMPs exhibits a similar pattern of expression
(3, 4, 5, 6, 7)
. Thus, MT1-MMP and MT2-MMP are widely expressed in
a variety of adult human tissues, whereas MT3-MMP, MT4-MMP, and
MT5-MMP, which display a more restricted expression pattern, are
abundantly expressed in brain, a tissue lacking any significant levels
of MT6-MMP transcripts. On this basis, it is tempting to speculate that
this novel membrane proteinase could play some specific role in
membrane activation of specific substrates or in any of the connective
tissue remodeling processes occurring in those tissues in which its
levels are higher than those of the remaining MT-MMPs. A similar
situation may occur in the case of MT-MMP expression in malignant
tumors. In fact, in this study, we have provided evidence that MT6-MMP
is expressed at high levels in SW480 colon carcinoma cells, whereas no
expression is detected in normal colon. Furthermore, MT6-MMP is also
expressed in several brain tumors, including anaplastic astrocytomas
and glioblastomas. In marked contrast, samples from normal brain or
meningiomas did not show any significant levels of MT6-MMP RNA
transcripts. These findings suggest that MT6-MMP may be somewhat linked
to the malignant transformation of some cell types and provides
additional interest in the further functional characterization of this
protease. In this regard, it is remarkable that a comparative analysis
of the expression of several MT-MMPs in the same panel of brain tumors
did reveal distinctive patterns for all of them. These data suggest
that different tumors may use different MT-MMPs to activate
progelatinase A or other alternative substrates at the plasma membrane
as part of a general mechanism to facilitate tumor progression.
In conclusion, we have identified and characterized a new MT-MMP that shows similarities and differences with the remaining members of this subfamily of MMPs. MT6-MMP exhibits all structural features characteristic of these membrane-bound proteases, as well as a profile of activity against progelatinase A, which is typical of these enzymes. However, its chromosomal location and expression pattern distinguish this enzyme from other family members. Furthermore, the pattern of expression in cancer cell lines and brain tumors is also distinct from other MT-MMPs. Additional studies will be required to elucidate the biological significance of this protein in normal processes as well as its putative implication in the cell surface focusing of proteolytic activities during invasive growth of tumor cells.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by grants from Comisión
Interministerial de Ciencia y Tecnología-Spain (SAF97-0258),
Plan-Feder (Spain), and EU-BIOMED II (BMH4-CT96-0017). 
2 To whom requests for reprints should be
addressed, at Departamento de Bioquímica y Biología Molecular,
Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain.
Phone: 34-985-104201; Fax: 34-985-103564; E-mail: CLO{at}correo.uniovi.es
3 The abbreviations used are: MMP, matrix
metalloproteinase; MT-MMP, membrane-type MMP; HA, hemagglutinin;
poly(A)+, polyadenylated; FMF, familial Mediterranean
fever.
Received 11/29/99. Accepted 12/30/99.
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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]
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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]
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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]
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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]
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 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]
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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]
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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]
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 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]
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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]
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 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]
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 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]
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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]
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 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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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