Non-proteolytic, Receptor/Ligand Interactions Associate Cellular Membrane Type-1 Matrix Metalloproteinase with the Complement Component C1q

Rozanov, Dmitri V.; Sikora, Sergey; Godzik, Adam; Postnova, Tatiana I.; Golubkov, Vladislav S.; Savinov, Alexei Y.; Tomlinson, Stephen; Strongin, Alex Y.

doi:10.1074/jbc.m409174200

Cited by 20 publications

(16 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These sequence regions are spatially distant from the protease's active site. As a result, the catalytically active and the catalytically latent forms of cellular MT1-MMP are both efficient in binding with C1q [120]. In agreement, despite the MT1-MMP•C1q interactions, C1q is totally resistant to MT1-MMP proteolysis.…”

Section: Mt1-mmpsupporting

confidence: 58%

Mislocalization and unconventional functions of cellular MMPs in cancer

Strongin

2006

Cancer Metastasis Rev

Self Cite

View full text Add to dashboard Cite

MMPs are multifunctional enzymes capable of targeting the extracellular matrix, growth factors, cytokines and cell surface-associated adhesion and signaling receptors. The cellular localization and the activity of MMPs are tightly controlled at both the transcriptional and the post-transcriptional levels. Mislocalization and presentation in unconventional cellular compartments provide MMPs with an opportunity to cleave previously unidentified proteins. This review is focused on two, entirely different MMPs, one of which is membrane-tethered and another of which is soluble (MT1-MMP and MMP-26, respectively) from twenty four known human MMPs. Our recent studies determined that both of these enzymes functioned at unexpected cellular compartments and it was resulted in the identification of novel proteolytic pathways, whose significance we only partially comprehend as of this writing. It is reasonable, however, to hypothesize from these data that many individual MMPs perform in a similar manner and display a much broader range of functions compared to what we earlier thought.

show abstract

Section: Mt1-mmpsupporting

confidence: 58%

Mislocalization and unconventional functions of cellular MMPs in cancer

Strongin

2006

Cancer Metastasis Rev

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several individual MMPs, including MMP-1, MMP-3, MMP-7, MMP-9, MMP-26, and MT1-MMP, have been reported to cleave AAT and to destroy its serpin activity (35)(36)(37)(38)(39)(40). The individual MMPs cleave 55-kDa AAT near the C terminus and generate the 51-kDa N-terminal fragment as well as a C-terminal fragment of ϳ4 kDa (38).…”

Section: Figure 3 Analysis Of Cellular Mt6-mmpmentioning

confidence: 99%

Biochemical Characterization of the Cellular Glycosylphosphatidylinositol-linked Membrane Type-6 Matrix Metalloproteinase

Radichev

Remacle

Shiryaev

et al. 2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Ubiquitously expressed membrane type-1 matrix metalloproteinase (MT1-MMP), an archetype member of the MMP family, binds tissue inhibitor of metalloproteinases-2 (TIMP-2), activates matrix metalloproteinase-2 (MMP-2), and stimulates cell migration in various cell types. In contrast with MT1-MMP, the structurally similar MT6-MMP associates with the lipid raft compartment of the plasma membrane using a GPI anchor. As a result, MT6-MMP is functionally distinct from MT1-MMP. MT6-MMP is insufficiently characterized as yet. In addition, a number of its biochemical features are both conflicting and controversial. To reassess the biochemical features of MT6-MMP, we have expressed the MT6-MMP construct tagged with a FLAG tag in breast carcinoma MCF-7 and fibrosarcoma HT1080 cells. We then used phosphatidylinositol-specific phospholipase C to release MT6-MMP from the cell surface and characterized the solubilized MT6-MMP fractions. We now are confident that cellular MT6-MMP partially exists in its complex with TIMP-2. Both TIMP-1 and TIMP-2 are capable of inhibiting the proteolytic activity of MT6-MMP. MT6-MMP does not stimulate cell migration. MT6-MMP, however, generates a significant level of gelatinolysis of the fluorescein isothiocyanatelabeled gelatin and exhibits an intrinsic, albeit low, ability to activate MMP-2. As a result, it is exceedingly difficult to record the activation of MMP-2 by cellular MT6-MMP. Because of its lipid raft localization, cellular MT6-MMP is inefficiently internalized. MT6-MMP is predominantly localized in the cell-tocell junctions. Because MT6-MMP has been suggested to play a role in disease, including cancer and autoimmune multiple sclerosis, the identity of its physiologically relevant cleavage targets remains to be determined. The members of the matrix metalloproteinase (MMP)2 family degrade a wide spectrum of extracellular matrix proteins, growth factors, and cell receptors and play important roles in multiple diseases (1-3). In malignancy, MMPs, especially membrane-type MMPs (MT-MMPs), have been proposed to play key roles in tumor invasion and metastasis (4). As a result, it is now accepted that in depth mechanistic understanding of the MT-MMP functionality will ultimately lead to novel and effective therapies against invasive, metastatic malignancies (5).The (1, 4). In contrast, the attachment of MT4-MMP and MT6-MMP to the plasma membrane takes place via a glycosylphosphatidylinositol (GPI) moiety that directs these proteinases to the caveola-enriched lipid raft compartment (6). Although there is a significant level of knowledge of the structural-functional relationships and regulation of MT1-MMP, an archetype member of the subfamily, exceedingly little is known about the biochemical and cellular properties of GPI-linked MT4-MMP and especially MT6-MMP. Originally, MT6-MMP was cloned from a fetal liver cDNA library and from leukocytes (7-9). Because of its abundance in leukocytes, the protease has also been called leukolysin. MT6-MMP was also found to be abnormally expressed by colon...

show abstract

“…Our recent data suggested that MT1-MMP, in addition to its pericellular proteolytic function (18,19), protects malignant cells from complement-mediated cytotoxicity (20). We have also determined that the His 171 -Glu-Lys-Gln-Ala-Asp 176 and Val 223 -Arg-Asn 224 peptide sequences of the catalytic domain of MT1-MMP are directly involved in binding with the complement component C1q (21). Both sequence regions are spatially distant from the active site of MT1-MMP; therefore, whether active or inactive, the protease species efficiently bind but do not cleave C1q.…”

Section: Introductionmentioning

confidence: 96%

Interference with the Complement System by Tumor Cell Membrane Type-1 Matrix Metalloproteinase Plays a Significant Role in Promoting Metastasis in Mice

Rozanov¹,

Savinov²,

Golubkov³

et al. 2006

Cancer Research

Self Cite

View full text Add to dashboard Cite

Neoplasms have developed strategies to protect themselves against the complement-mediated host immunity. Invasionand metastasis-promoting membrane type-1 (MT1) matrix metalloproteinase (MMP) is strongly associated with many metastatic cancer types. The relative importance of the individual functions of MT1-MMP in metastasis was, however, unknown. We have now determined that the expression of murine MT1-MMP in murine melanoma B16F1 cells strongly increased the number of metastatic loci in the lungs of syngeneic C57BL/6 mice. In contrast, MT1-MMP did not affect the number of metastatic loci in complement-deficient C57BL/6-C3 À/À mice. Our results indicated, for the first time, that the anticomplement activity of MT1-MMP played a significant role in promoting metastasis in vivo and determined the relative importance of the anticomplement activity in the total metastatic effect of this multifunctional proteolytic enzyme. We believe that our results shed additional light on the functions of MT1-MMP in cancer and clearly make this protease a promising drug target in metastatic malignancies.

show abstract

Non-proteolytic, Receptor/Ligand Interactions Associate Cellular Membrane Type-1 Matrix Metalloproteinase with the Complement Component C1q

Cited by 20 publications

References 48 publications

Mislocalization and unconventional functions of cellular MMPs in cancer

Mislocalization and unconventional functions of cellular MMPs in cancer

Biochemical Characterization of the Cellular Glycosylphosphatidylinositol-linked Membrane Type-6 Matrix Metalloproteinase

Interference with the Complement System by Tumor Cell Membrane Type-1 Matrix Metalloproteinase Plays a Significant Role in Promoting Metastasis in Mice

Contact Info

Product

Resources

About