Membrane-type Matrix Metalloproteinases (MT-MMP)s: Expression and Function During Glioma Invasion

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Abstract
Membrane-type MMPs (MT-MMPs) constitute a growing subclass of recently identified matrix metalloproteinases (MMPs). In addition to the highly conserved MMP functional domains, the MT-MMPs have additional insertion sequences (IS) that confer unique functional roles. While most of the MMPs are secreted, the MT-MMPs are membrane associated and a number of these have cytoplasmic domains which may be important in cellular signaling. This membrane localization leads to focal areas of receptor recruitment and subsequent activity, thereby enhancing pericellular proteolysis in specific areas of contact within the brain interstitium. MT1-MMP is the best-characterized MT-MMP, the measure against which subsequently cloned homologues are compared. MT1-MMP activates proMMP2 via its interaction with TIMP2, which serves as an intermolecular bridge for proMMP2 binding to MT-MMPs. In addition to activation of proMMP2, MT-MMPs display intrinsic proteolytic activity towards extracellular matrix molecules (ECM), which is independent of MMP2 activation. The increased expression levels of several members of the MMP family have been shown to correlate with high-grade gliomas, including MT1-MMP. Despite improvements in the diagnosis and treatment of patients with glial tumors, they remain the most common and least curable brain cancer in adults. The ability of glioma cells to infiltrate surrounding brain tissue, and ultimately escape current therapeutic modalities, could potentially be minimized using anti-invasive therapies. Proteolysis is a necessary part of the invasion process, within which the MT-MMPs appear to play a central role. The development of pharmaceutical approaches that target expression and regulation of MT-MMPs may prove beneficial in targeting invading glioma cells.

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