Membrane-type-1 matrix metalloproteinase confers tumorigenicity on nonmalignant epithelial cells

Soulié, Priscilla; Carrozzino, Fabio; Pepper, Michael Sean; Strongin, Alex Y.; Poupon, Marie‐France; Montesano, Roberto

doi:10.1038/sj.onc.1208360

Cited by 42 publications

(45 citation statements)

References 49 publications

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“…We also examined the effect of expressing MT1-MMP in SCC cells on the surrounding stroma using trichrome stain to label the collagen present in these tumors. Consistent with previously published reports demonstrating that MT1-MMP can induce fibrosis in vivo (62,63), SCC25-tet-MT and SCC25-tet-DC cells also induced a pronounced fibrotic reaction with increased collagen content as demonstrated by increased trichrome (blue) stain (Fig. 8C).…”

Section: Mt1-mmp Increases Cellular Aggregation and Myosin IIsupporting

confidence: 80%

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

Dangi-Garimella

Redig

Shields

et al. 2010

Journal of Biological Chemistry

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Matrix metalloproteinases (MMPs) 2 are a large family of highly conserved metalloendopeptidases with proteolytic activity directed against a variety of extracellular matrix (ECM) substrates (1-3). MMPs have been implicated in basement membrane proteolysis, activation of growth factors, and cleavage of cell-adhesion molecules. Extending mechanistic investigation to cancer biology, numerous studies have shown that MMP overexpression enhances the invasive activity of tumor cell lines (4 -6). Analysis of human disease further supports the pro-tumorigenic role of MMPs, as increased expression of these proteases in tumor samples is clinically associated with invasion, metastasis, poor prognosis, and shorter survival times (7,8). In the specific case of squamous cell carcinoma (SCC), increased expression of membrane type 1-MMP (MT1-MMP, MMP14) is associated with ECM breakdown, tissue invasion, and lymph node metastasis (8).However, several animal studies have now clearly demonstrated that multiple members of the MMP family provide a paradoxically protective effect during the relentless molecular destruction that characterizes malignant progression. MMPs may have been initially identified as potent pro-tumorigenic proteases, but their simultaneous ability to function in an opposing, anti-tumorigenic role is now equally well established (9, 10). Such data underscore both the complexity of MMP activity in cellular signaling events as well as the importance of stringently evaluating the context in which these proteases take on either an anti-tumorigenic or pro-tumorigenic role. Intriguingly, several recent studies using SCC models have begun to suggest a putative mechanism through which MMPs may be induced to function primarily as anti-tumorigenic proteases. When exposed to carcinogens, MMP3-null mice developed squamous cell skin cancers that not only grew faster but were also strikingly less differentiated than those of control animals (11). Significantly, orthotopic injection of MMP3-expressing tumor cells resulted in pronounced tumor cell differentiation (12). However, although such findings indicate that MMPs may inhibit SCC progression by promoting tumor cell differentiation, the precise mechanism through which these proteinases regulate this process has not yet been elucidated.In normal tissue keratinocyte differentiation is a complex process mediated by cell-ECM and cell-cell interactions that subsequently activate downstream signaling pathways (13-15). Specifically, among structural proteins, integrins mediate primarily cell-ECM interactions, whereas cadherins are responsible for cell-cell interactions (13). In vitro activation of integrins or inhibition of cadherins after ligation or dominant negative expression, respectively, results in negative regulation of human keratinocyte differentiation (16 -18). Furthermore, beyond structural proteins, Rho GTPases are also known to be an important component of keratinocyte differentiation pathways. Rho signaling has been shown to mediate cell-cell and cell-matrix adhesion...

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Section: Mt1-mmp Increases Cellular Aggregation and Myosin IIsupporting

confidence: 80%

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

Dangi-Garimella

Redig

Shields

et al. 2010

Journal of Biological Chemistry

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“…The expression of MT1-MMP in the centrosomes of either human or canine cells correlated with the presence of the proteolytic fragments of pericentrin. In addition, these events correlated with the induction of mitotic spindle aberrations and aneuploidy in non-malignant MDCK cells (18,23). The sequence alignment of the putative cleavage site in human and canine pericentrin (ALRRLLG 1156 2L 1157 FG and ALRRLLS 2068 2L 2069 FG, respectively) supported our biochemical and cellular experiments, because both Gly and Ser are compatible with the known cleavage preferences of MT1-MMP.…”

Section: Discussionsupporting

confidence: 62%

“…The presence of MT1-MMP in the pericentrosomal space correlated with the cleavage of human pericentrin-2 (kendrin), an integral and functionally important centrosomal, 3336-amino-acid residue long, protein (19 -22), and chromosome instability in non-malignant epithelial Madin-Darby canine kidney cells (18,23). Centrosomes, spindle pole bodies, are cellular organelles that exhibit an ability to organize microtubules and to nucleate (24).…”

Section: Mt1-mmpmentioning

confidence: 99%

Centrosomal Pericentrin Is a Direct Cleavage Target of Membrane Type-1 Matrix Metalloproteinase in Humans but Not in Mice

Golubkov

Chekanov

Doxsey

et al. 2005

Journal of Biological Chemistry

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Membrane type-1 matrix metalloproteinase (MT1-MMP) exhibits distinctive and important pericellular cleavage functions. Recently, we determined that MT1-MMP was trafficked to the centrosomes in the course of endocytosis. Our data suggested that the functionally important, integral, centrosomal protein, pericentrin-2, was a cleavage target of MT1-MMP in human and in canine cells and that the sequence of the cleavage sites were ALRRLLG 1156 2L 1157 FG and ALRRLLS 2068 2L 2069 FG, respectively. The presence of Asp-948 at the P1 position inactivated the corresponding site (ALRRLLD 948 -L 949 FGD) in murine pericentrin. To confirm that MT1-MMP itself cleaves pericentrin directly, rather than indirectly, we analyzed the cleavage of the peptides that span the MT1-MMP cleavage site. In addition, we analyzed glioma U251 cells, which co-expressed MT1-MMP with the wild type murine pericentrin and the D948G mutant. We determined that the D948G mutant that exhibited the cleavage sequence of human pericentrin was sensitive to MT1-MMP, whereas unmodified murine pericentrin was resistant to proteolysis. Taken together, our results confirm that MT1-MMP cleaves pericentrin-2 in humans but not in mice and that mouse models of cancer probably cannot be used to critically examine MT1-MMP functionality. MT1-MMP2 /MMP-14 is a prototypic member of the membranetethered matrix metalloproteinases (1). Although MT1-MMP is present in normal tissues, its enhanced expression is directly linked to tumor progression and metastasis (2-6). Cell surface-associated MT1-MMP is a multifunctional enzyme (7), and it is involved in the pericellular proteolysis of the extracellular matrix, the activation of soluble MMPs, and the cleavage of adhesion and signaling cell receptors (8 -10). The functional activity of MT1-MMP is regulated by its activation by furinlike proprotein convertases, by its inhibition by TIMPs, and by its selfproteolysis and shedding (11-13). Evidence is also emerging that exocytosis, endocytosis, and recycling also regulate the presentation of MT1-MMP on the cell surface and, consequently, its cell surface-associated proteolytic activity (14 -17).Recently, we determined that functionally active MT1-MMP, which was presented on the cell surface, was internalized, trafficked alongside the microtubular cytoskeleton, and delivered to the centrosomal compartment (16,18). The presence of MT1-MMP in the pericentrosomal space correlated with the cleavage of human pericentrin-2 (kendrin), an integral and functionally important centrosomal, 3336-amino-acid residue long, protein (19 -22), and chromosome instability in non-malignant epithelial Madin-Darby canine kidney cells (18,23). Centrosomes, spindle pole bodies, are cellular organelles that exhibit an ability to organize microtubules and to nucleate (24). The normal functionality of centrosomes is essential to the organization of the cytoskeleton and the mitotic spindle, self-duplication, and cell cycle progression (25, 26). Conversely, centrosomal abnormalities, early predictors of carcinog...

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“…In an efficient, but not yet completely understood manner, MT1-MMP acts as a growth factor in malignant cells and assumes tumor growth control (Hotary et al, 2003;Koshikawa et al, 2005). Our previous work has clearly shown that MT1-MMP confers tumorigenicity on non-malignant epithelial cells, thus providing us with substantive evidence of the enormous importance of this protease in cell functioning and, probably, in malignant transformation (Soulie et al, 2004).…”

Section: Discussionmentioning

confidence: 91%

The transmembrane domain is essential for the microtubular trafficking of membrane type-1 matrix metalloproteinase (MT1-MMP)

Remacle

Rozanov

Baciu

et al. 2005

Journal of Cell Science

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Membrane type-1 matrix metalloproteinase (MT1-MMP) degrades the extracellular matrix, initiates the activation pathway of soluble MMPs and regulates the functionality of cell adhesion signaling receptors, thus playing an important role in many cell functions. Intracellular transport mechanisms, currently incompletely understood, regulate the presentation of MT1-MMP at the cell surface. We have focused our efforts on identifying these mechanisms. To understand the transport of MT1-MMP across the cell, we used substitution and deletion mutants, the trafficking of which was examined using antibody uptake and Chariot delivery experiments. Our experiments have demonstrated that the microtubulin cytoskeleton and the centrosomes (the microtubulin cytoskeleton-organizing centers) are essential for the trafficking and the internalization of MT1-MMP. We determined that after reaching the plasma membrane, MT1-MMP is internalized in the Rab-4-positive recycling endosomes and the Rab-11-positive pericentrosomal recycling endosomes. The microtubular trafficking causes the protease to accumulate in the pericentrosomal region of the cell. We believe that the presence of the transmembrane domain is required for the microtubular vesicular trafficking of MT1-MMP because the soluble mutants are not presented at the cell surface and they are not delivered to the centrosomes. The observed transport mechanisms provide a vehicle for the intracellular targets and, accordingly, for an intracellular cleavage function of MT1-MMP in malignant cells, which routinely overexpress this protease.

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Membrane-type-1 matrix metalloproteinase confers tumorigenicity on nonmalignant epithelial cells

Cited by 42 publications

References 49 publications

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

Centrosomal Pericentrin Is a Direct Cleavage Target of Membrane Type-1 Matrix Metalloproteinase in Humans but Not in Mice

The transmembrane domain is essential for the microtubular trafficking of membrane type-1 matrix metalloproteinase (MT1-MMP)

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