Differential Inhibition of Membrane Type 3 (MT3)-Matrix Metalloproteinase (MMP) and MT1-MMP by Tissue Inhibitor of Metalloproteinase (TIMP)-2 and TIMP-3 Regulates Pro-MMP-2 Activation

Abstract

The matrix metalloproteinases (MMPs), 1 a multidomain family of zinc-dependent endopeptidases, degrade all structural components of the extracellular matrix (ECM) and many bioactive molecules, thereby playing essential roles in many physiological and pathological processes (1-4). Based on structural organization and subcellular localization, the MMP family is divided into secreted and membrane-anchored enzymes (1, 5). The membrane type-MMPs (MT-MMPs) comprise six members of plasma membrane-tethered MMPs, which include four type I transmembrane enzymes: MT1-, MT2-, MT3-, and MT5-MMP, and two glycosylphosphatidylinositol-anchored enzymes: MT4-and MT6-MMP (4, 6 -8). Although there is some tissue-specific expression of MT-MMPs, there is also significant overlap both in expression and in function raising the question of how cells command the repertoire of MT-MMPs at their disposition during proteolytic events. A major mechanism for controlling MT-MMP activity in the pericellular space is mediated by the action of tissue inhibitors of metalloproteinases (TIMPs). However, as opposed to soluble MMPs, which are almost equally inhibited by all TIMPs (9, 10), the MT-MMPs are highly selective when it comes to TIMP interactions. For example, the type I transmembrane MT-MMPs are poorly inhibited by TIMP-1 but are relatively well inhibited by TIMP-2, TIMP-3, and TIMP-4. In contrast, the glycosylphosphatidylinositol-anchored MT-MMPs are inhibited by both TIMP-1 and TIMP-2 (11). The differential sensitivity to TIMP inhibition among members of the MT-MMP family may facilitate the control of MT-MMP activity in the pericellular space.In addition to being potent ECM-degrading enzymes, the type I transmembrane MT-MMPs can also initiate a cascade of zymogen activation on the cell surface. MT-MMPs activate the zymogenic form of MMP-2 (pro-MMP-2 or pro-gelatinase A) (6, 8), which in turn can activate pro-MMP-9 (pro-gelatinase B) (12). MT1-MMP also promotes the activation of pro-collagenase 3 (MMP-13) (13), a potent collagenolytic protease. Because the gelatinases are efficient gelatinolytic enzymes, the MT-MMP/ MMP-13/gelatinase axis represents a well adapted proteolytic system designed to promote coordinated and complete collagen degradation in the pericellular space. Although the type I

Tissue Inhibitor of Metalloproteinases Protect Blood—Brain Barrier Disruption in Focal Cerebral Ischemia

“…However, No differences between MMP-2 gene knockout mice and WT mice were observed, thereby its contribution to ischemic injury remains to be validated (Asahi et al, 2001a). Secreted latent MMP-2 is activated by TIMP-2 and MT-MMPs through a unique process (Zhao et al, 2004). Activated MMP-2 is then naturally inhibited by TIMPs.…”

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

“…Protease activity analysis by gelatin zymography and gene expression array Basal MMP-2 and MMP-9 activities were detected using gelatin zymography as previously described (Zhao et al, 2004). Serum-starved cells were grown in the presence of periostin for 24 h and then supernatants were collected, precleared and concentrated before application of 10 mg of protein on a 10% Novex gel containing 0.1% gelatin (Invitrogen Corp).…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…TIMP-3 also enhances the activation of pro-MMP-2 by MT3-MMP but not by MT1-MMP. On the other hand, TIMP-4 cannot support pro-MMP-2 activation with either enzyme (Zhao et al, 2004). Pro-MMP-2 can assemble trimolecular complexes with a catalytic domain of MT3-MMP and TIMP-2 or TIMP-3 suggesting that pro-MMP-2 activation by MT3-MMP involves ternary complex formation on the cell surface.…”

“…Pro-MMP-2 can assemble trimolecular complexes with a catalytic domain of MT3-MMP and TIMP-2 or TIMP-3 suggesting that pro-MMP-2 activation by MT3-MMP involves ternary complex formation on the cell surface. TIMP-3 is a major regulator of MT3-MMP activity and further underscores the unique interactions of TIMPs with MT-MMPs in the control of pericellular proteolysis (Zhao et al, 2004).…”

“…Inhibitor profile and MMP-16 mutant enzyme studies indicate that MT3-MMP is regulated on the cell surface by the autocatalytic processing and the ectodomain shedding (Zhao et al, 2004). MT1-MMP and MT3-MMP can process the membraneanchored proteoglycan betaglycan (sBG-120) that binds transforming growth factor-b (TGF-b) via its core protein, generating a 90-kDa fragment .…”