MT4-MMP: The GPI-Anchored Membrane-Type Matrix Metalloprotease with Multiple Functions in Diseases.

MT4-MMP (or MMP17) belongs to the Membrane-Type Matrix Metalloproteinase (MT-MMP) family. This family of proteases contributes to extracellular matrix remodeling during several physiological processes, including embryogenesis, organogenesis, tissue regeneration, angiogenesis, wound healing, and inflammation. MT4-MMP (MMP17) presents unique characteristics compared to other members of the family in terms of sequence homology, substrate specificity, and internalization mode, suggesting distinct physiological and pathological functions. While the physiological functions of MT4-MMP are poorly understood, it has been involved in different pathological processes such as arthritis, cardiovascular disease, and cancer progression. The mt4-mmp transcript has been detected in a large diversity of cancers. The contribution of MT4-MMP to tumor development has been further investigated in gastric cancer, colon cancer, head and neck cancer, and more deeply in breast cancer. Given its contribution to different pathologies, particularly cancers, MT4-MMP represents an interesting therapeutic target. In this review, we examine its biological and structural properties, and we propose an overview of its physiological and pathological functions.

Membrane-type 6 matrix metalloproteinase regulates the activation-induced downmodulation of CD16 in human primary NK cells.

CD16 (FcγRIIIa), the low-affinity receptor for IgG, expressed by the majority of human NK cells, is a potent activating receptor that facilitates Ab-dependent cell-mediated cytotoxicity (ADCC). ADCC dysfunction has been linked to cancer progression and poor prognosis for chronic infections, such as HIV; thus, understanding how CD16 expression is regulated by NK cells has clinical relevance. Importantly, CD16 cell-surface expression is downmodulated following NK cell activation and, in particular, exposure to stimulatory cytokines (IL-2 or IL-15), likely owing to the action of matrix metalloproteinases (MMPs). In this article, we identify membrane-type 6 (MT6) MMP (also known as MMP25) as a proteinase responsible for CD16 downmodulation. IL-2-induced upregulation of MT6/MMP25 cell-surface expression correlates with CD16 downmodulation. MT6/MMP25, sequestered in intracellular compartments in unstimulated NK cells, translocates to the cell surface after stimulation; moreover, it polarizes to the effector-target cell interface of the CD16-mediated immunological synapse. siRNA-mediated disruption of MT6/MMP25 expression enhances the ADCC capacity of NK cells, emphasizing the important functional role of MT6/MMP25 in the regulation of ADCC activity. Thus, this study uncovers a previously unknown role of MT6/MMP25 in human NK cells, and suggests that inhibition of MT6/MMP25 activity could improve ADCC efficacy of therapeutically administered NK cells that require IL-2 for culture and expansion.

Retinal ganglion cells with distinct directional preferences differ in molecular identity, structure, and central projections.

The retina contains ganglion cells (RGCs) that respond selectively to objects moving in particular directions. Individual members of a group of ON-OFF direction-selective RGCs (ooDSGCs) detect stimuli moving in one of four directions: ventral, dorsal, nasal, or temporal. Despite this physiological diversity, little is known about subtype-specific differences in structure, molecular identity, and projections. To seek such differences, we characterized mouse transgenic lines that selectively mark ooDSGCs preferring ventral or nasal motion as well as a line that marks both ventral- and dorsal-preferring subsets. We then used the lines to identify cell surface molecules, including Cadherin 6, CollagenXXVα1, and Matrix metalloprotease 17, that are selectively expressed by distinct subsets of ooDSGCs. We also identify a neuropeptide, CART (cocaine- and amphetamine-regulated transcript), that distinguishes all ooDSGCs from other RGCs. Together, this panel of endogenous and transgenic markers distinguishes the four ooDSGC subsets. Patterns of molecular diversification occur before eye opening and are therefore experience independent. They may help to explain how the four subsets obtain distinct inputs. We also demonstrate differences among subsets in their dendritic patterns within the retina and their axonal projections to the brain. Differences in projections indicate that information about motion in different directions is sent to different destinations.

Matrilysins may not predict the metastatic potential in squamous cell carcinoma of the tongue.

OBJECTIVE: To examine immunoexpression of matrix metalloproteinase (MMP)-7 and -26 in squamous cell carcinoma (SCC) of the tongue and its relation with cervical metastasis. MATERIAL AND METHODS: Twenty-four cases were selected and divided into two groups: a metastatic group (n = 12) and a non-metastatic group (n = 12). Cases were graded as either negative (score 0), positive (score +) or strongly positive (score ++). RESULTS: MMP-7 expression was identical in both groups, with 17% of the cases graded as score 0, 50% as score + and 33% as score ++. MMP-26 expression was 25% score 0, 8% score + and 67% score ++ in the metastatic group, and 8% score 0, 50% score + and 42% score ++ in the non-metastatic group. Statistical analysis showed no differences between the studied groups and no correlations between proteins. CONCLUSIONS: MMP-7 and -26 immunostaining is not a useful indicator of the metastatic potential of SCCs of the tongue. However, the role of these proteins in the process of invasion and metastasis cannot be ruled out since their more marked presence along the tumor invasion front compared to more central areas of the tumors indicates higher secretion of these proteases in this region, facilitating the invasion process.

Identification of a novel human MT5-MMP transcript variant in multipotent NT2 cells.

Membrane-type 5 matrix metalloproteinase (MT5-MMP) expression is ubiquitous in brain development while restricted to regions of neuroplasticity in adult. In the multipotent NT2 model of neurogenesis and differentiation, MT5-MMP is differentially expressed with significantly higher mRNA levels in the differentiated neuronal hNT cells. MT5-MMP cDNA cloned from NT2 cells unexpectedly revealed a novel sequence (MT5-MMPvar) characterized by a 162bp deletion. Both transcripts were identified in NT2, hNT and adult human hippocampus. In vitro, MT5-MMPvar translated into a approximately 55 kDa protein. It was also detected in NT2, hNT and adult human hippocampus. These results suggest more than one human MT5-MMP transcript may exist in the central nervous system.

Downregulation of membrane type-matrix metalloproteinases in the inflamed or injured central nervous system.

BACKGROUND: Matrix metalloproteinases (MMPs) are thought to mediate cellular infiltration in central nervous system (CNS) inflammation by cleaving extracellular matrix proteins associated with the blood-brain barrier. The family of MMPs includes 23 proteinases, including six membrane type-MMPs (MT-MMPs). Leukocyte infiltration is an integral part of the pathogenesis of autoimmune inflammation in the CNS, as occurs in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE), as well as in the response to brain trauma and injury. We have previously shown that gene expression of the majority of MMPs was upregulated in the spinal cord of SJL mice with severe EAE induced by adoptive transfer of myelin basic protein-reactive T cells, whereas four of the six MT-MMPs (MMP-15, 16, 17 and 24) were downregulated. The two remaining MT-MMPs (MMP-14 and 25) were upregulated in whole tissue. METHODS: We used in vivo models of CNS inflammation and injury to study expression of MT-MMP and cytokine mRNA by real-time RT-PCR. Expression was also assessed in microglia sorted from CNS by flow cytometry, and in primary microglia cultures following treatment with IFNgamma. RESULTS: We now confirm the expression pattern of MT-MMPs in the B6 mouse, independent of effects of adjuvant. We further show expression of all the MT-MMPs, except MMP-24, in microglia. Microglia isolated from mice with severe EAE showed statistically significant downregulation of MMP-15, 17 and 25 and lack of increase in levels of other MT-MMPs. Downregulation of MT-MMPs was also apparent following CNS injury. The pattern of regulation of MT-MMPs in neuroinflammation showed no association with expression of the proinflammatory cytokines TNFalpha, IL-1beta, or IFNgamma. CONCLUSION: CNS inflammation and injury leads to downregulation in expression of the majority of MT-MMPs. Microglia in EAE showed a general downregulation of MT-MMPs, and our findings suggest that MT-MMP levels may inversely correlate with microglial reactivity.

Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration.

Wnts are a family of secreted glycoproteins with diverse developmental roles, including regulation of cell migration; however, little is known about wnt signaling in mature T cells. We find that endothelial-cell-derived wnts, acting through Frizzled receptors, induce matrix metalloproteinase (MMP) 2 and MMP9 expression in effector T cells. Blocking wnt signaling, or MMP activity, reduces T cell migration through the basement membrane in vitro and into inflamed skin in vivo. Wnt signaling stabilizes beta-catenin protein in T cells and directly targets the MMP promoters through tandem TCF sites. Thus, our data support a necessary and previously unexpected role for wnt signaling in T cell extravasation.

Construction of antisense MT1-MMP vector and its inhibitory effects on invasion of human ovarian cancer cells.

Membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP-14) plays crucial roles in tumor cell growth, invasion, and angiogenesis. To clarify whether the endogenously expressed MT1-MMP in metastatic human ovarian carcinoma cell lines SKOV3 plays a critical role in tumor cell invasiveness, antisense MT1-MMP cloned in eukaryotic expression vector pMMP14as was transferred into SKOV3 cells. 48h after transfection, decreased expression of endogenous MT1-MMP protein was detected in pMMP14as-transfected SKOV3 cells and the activation of pro-MMP2 was inhibited markedly. The mean percentage of invasive cells was (62.50 +/- 5.30) % in pMMP14as-transfected cells, which was obviously less than that (97.20 +/- 6.90) % in the control. Thus, antisense MT1-MMP effectively inhibited the endogenous MT1-MMP expression and the invasiveness in SKOV3 cells, suggesting that MT1-MMP may be a therapeutic target molecule for human invasive ovarian cancers.