Cellular Activation of MMP-2 (Gelatinase A) by MT2-MMP Occurs via a TIMP-2-independent Pathway

Morrison, Chet A.; Butler, Georgina S.; Bigg, Heather F.; Roberts, Clive J.; Soloway, Paul D.; Overall, Christopher M.

doi:10.1074/jbc.m108643200

Cited by 159 publications

(152 citation statements)

References 52 publications

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“…Examples hereof are proMMP-2 activation by thrombin in a MT1-MMP dependent manner [41] and activation of proMMP-2 by MT2-MMP in a TIMP-2 independent manner [42]. The complexity of the different activation mechanisms indicates however, that there is a complicated network regulating extracellular matrix degradation.…”

Section: Activation Of Mmpsmentioning

confidence: 99%

The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia

Klein

Vellenga

Fraaije

et al. 2004

Critical Reviews in Oncology/Hematology

308

170

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Section: Activation Of Mmpsmentioning

confidence: 99%

The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia

Klein

Vellenga

Fraaije

et al. 2004

Critical Reviews in Oncology/Hematology

308

170

View full text Add to dashboard Cite

“…However, the requirement for TIMP-2 in pro-MMP2 activation by MT-MMPs 2-6 is less well known. Recently, Morrison et al (2001) reported that MT2-MMP efficiently activates MMP2 in a TIMP-2-inde-pendent pathway. …”

Section: Membrane-associated Mmpsmentioning

confidence: 99%

Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis

et al. 2003

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The matrix metalloproteinases (MMPs) constitute a multigene family of over 23 secreted and cell-surface associated enzymes that cleave or degrade various pericellular substrates. In addition to virtually all extracellular matrix (ECM) compounds, their targets include other proteinases, chemotactic molecules, latent growth factors, growth factor-binding proteins and cell surface molecules. The MMP activity is controlled by the physiological tissue inhibitors of MMPs (TIMPs). There is much evidence that MMPs and their inhibitors play a key role during extracellular remodeling in physiological situations and in cancer progression. They have other functions that promoting tumor invasion. Indeed, they regulate early stages of tumor progression such as tumor growth and angiogenesis. Membrane type MMPs (MT-MMPs) constitute a new subset of cell surface-associated MMPs. The present review will focus on MT1-MMP which plays a major role at least, in the ECM remodeling, directly by degrading several of its components, and indirectly by activating pro-MMP2. As our knowledge on the field of MT1-MMP biology has grown, the unforeseen complexities of this enzyme and its interaction with its inhibitor TIMP-2 have emerged, often revealing unexpected mechanisms of action.Keywords: MT1-MMP ; tumoral angiogenesis ; vascular endothelial growth factor ; protease inhibitors ; estradiol MMP structure and functionsMatrix metalloproteinases (MMPs) are a broad family of zinc-binding endopeptidases that play a key role in the extracellular matrix (ECM) degradation associated with cancer cell invasion, metastasis and angiogenesis (Egeblad and Werb, 2002;McCawley and Matrisian, 2000). At present, more than 21 human MMPs and the homologues from other species have been identified (Egeblad and Werb, 2002). The MMP family can be segregated into two groups, the soluble type and the membrane-type MMPs (MT-MMPs and MMP23). Although initially classified according to their substrate specificity (McCawley and Matrisian, 2000), the MMP classification is now based on their structure (Egeblad and Werb, 2002). The 'minimal-domain MMPs' (MMP7 and MMP26) contains (i) a signal peptide that directs them to the endoplasmic reticulum, (ii) a propeptide, with a zinc-interacting thiol (SH) group that maintains the proMMP in a latent form (zymogen), and (iii) a catalytic domain containing the highly conserved Zn 2+ binding site (HEXGHXXGXXHS/T) (Fig. 1). With the exception of MMP23, all other MMPs display a prolinerich hinge region that links the catalytic domain to the hemopexin/vitronectin-like domain. This C-terminal domain influences substrate specificity and the binding to tissue inhibitors of MMPs (TIMPs) and cell surface molecules. The hemopexin-containing MMPs are further distinguished by the presence of specific insert(s). The gelatin-binding MMPs (MMP2 and MMP9 or gelatinases) contain inserts that resemble the collagen-binding type II repeats of fibronectin. The membrane type (MT)-MMPs have a single pass transmembrane domain and a short cytoplasmic...

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“…Other receptors for gelatinases may also exist. MT2-MMP mediated activation of MMP-2 involves TIMP-independent C-terminal domain interactions on the cell surface, but the receptor has not been identified (Morrison et al, 2001).…”

Section: Cell Surface Associations Of the Gelatinasesmentioning

confidence: 99%