TIMPs metalloproteinases

The enzymatic activity of these potentially harmful enzymes is tightly controlled. Once transcribed into protein, MMPs are expressed as inactive zymogens and require distinct activation processes to convert them into active enzymes. After secretion, MMP-activity is regulated by the noncovalent binding of tissue inhibitors of metalloproteinases ( TIMPs) as shown in Fig. 2 for MMP-2 and TIMP-2. Four TIMPs have been identified so far TIMP-1, TIMP-2, TIMP-3, and TIMP-4. All known MMPs can be inhibited by at least one of the four known TIMPs. Nevertheless, individual differences with regard to bond strength and thus the magnitude of inhibition of a particular MMP do exist. 

Matrix Metalloproteinases. Figure 2 ProMMP-2-TIMP-2 structure (adopted from [4]). TIMP-2 cartoon and transparent surface structure is shown in blue, MMP-2 in red. The C-terminal ends of both molecules are marked as spheres. 

The matrix metalloproteinases are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors TIMP-1, TIMP-2, TIMP-3, and TIMP-4. Overall, all MMPs are inhibited by TIMPs once they are activated but the gelatinases (MMP-2 and MMP-9) can form complexes with TIMPs when the enzymes are in the latent form. 

Gelman BB, Wolf DA, Rodriguez-Wolf M et al (1997) Mononuclear phagocyte hydrolytic enzyme activity associated with cerebral HIV-1 infection. Am J Pathol 151 1437-1446 Giraudon P, Buart S, Bernard A et al (1997) Cytokines secreted by gUal cells infected with HTLV-I modulate the expression of matrix metalloproteinases (MMPs) and their natural inhibitor (TIMPs) possible involvement in neurodegenerative processes. Mol Psychiatry 2(107-10) 84... 

TIMP-1, TIMP-2 Tissue inhibitors of metalloproteinases 1 and 2 Ha Thymus leukaemia antigen TLC TTiin-layer chromatt raphy TLCK Tosyl-lysyl-CHiCl TLP Tumour-like proliferation Tm T memory... 

The hypothesis that stress can modulate MMP expression is also supported by studies in mice. Using social isolation as a stressor, the mRNA levels of MMP-2, MMP-9, matrix-type matrix metalloproteinase-1 (MT1-MMP), and urokinase-type plasminogen activator were higher in the tumor and liver tissues of the isolated mice than in control mice.91 Furthermore, a recent study has shown that restraint stress causes an increase in expression of the plasminogen activator inhibitor-1, another key player in the plas-minogen/plasmin enzyme system in mice.92 As these enzymes have been described to have functions besides their role in ECM remodeling,93 studies on stress-related effects on MMP/TIMP balance have implications in the relationship between stress and cancer initiation and progression.. 

Alexander, J., Samples, J., and Acott, T., Growth factor and cytokine modulation of trabecular meshwork matrix metalloproteinase and TIMP expression, Curr. Eye Res., 17, 276, 1998. 

KI3. Kossakouska, A. E., Urbanski, S. J., Huchcroft, S. A., and Edwards, R. R., Relationship between clinical aggressiveness of large cell immunoblastic lymphomas and expression of 92 kDa gelatinase (type IV collagenase) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Oncol. Res. 4, 233-240 (1992). 

TIMP Tissue inhibitor of metalloproteinase family. E(M) 0(0) 1(1) 1BR9... 

Although much has been learned ftom in vitro assays, we do not yet fully understand the predominant migratory mechanisms used by cancer cells in vivo. It is important that any molecular mediators (or their inhibitors) identified in one assay are tested in complementary assays and validated in appropriate in vivo models before they can be assumed to play a significant role in invasion and metastasis. There are several examples where a molecule can have either positive or negative regulatory roles in key cellular functions depending on the cellular/microenvironmental context (e.g., tissue inhibitors of matrix metalloproteinases TIMPs (12)). Thus, care needs to be taken to avoid undesirable activities or, as in the example of some angiogenic inhibitors, compensatory mechanisms that result in adverse events (13). 

The MMPs are secreted as inactive proenzymes, which are activated by proteolytic cleavage. Once activated they are subject to control by tissue inhibitors of metalloproteinases (TIMPs). It is the imbalance between the active enzymes and the TIMPs that leads to destructive tissue degradation that potent directed pharmaceuticals can overcome. These enzymes have been the target of... 

Another possible strategy that, to our knowledge, has not been studied is to increase the concentration or effect of matrix metalloproteinases, compounds that are responsible for controlled, ongoing degradation of collagen. One such method would be to block tissue inhibitors of metalloproteinases (TIMPs). Such a method would have... 

Abbreviations CEL, cellulose DXM, dexamethasone EIPA, ethylisopropylamiloride FIB, fibrin MR methylprednisolone NA, not available Neo-R, neointima reduction PC, phosphorylcholine PCL, polycaprolactone PFM-P75, polyfluoroalkoxyphosphazene PLLA(PLA), poly-L-lactic acid POP, polyorganophosphazene PU, polyurethane Q-DL, Quanam drug eluting stent Q-M, Quanam metal stent SNR sodium nitroprusside TIMP, tissue inhibitors of metalloproteinase. 

The MMPs are a family of zinc-dependent neutral endopep-tidases that share structural domains but differ in substrate specificity, cellular sources, and inductivity (Table I). All the MMPs are important for remodeling of the extra cellular matrix and share the following functional features (/) they degrade extracellular matrix components, including fibronectin, collagen, elastin, proteoglycans, and laminin, (//) they are secreted in a latent proform and require activation for proteolytic activity, (///) they contain zinc at their active site and need calcium for stability, (/V) they function at neutral pH, and (v) they are inhibited by specific tissue inhibitors of metalloproteinases (TIMPs). 

Cultured cells secrete hyaluronidases into the culture media, away from the cells. Such a phenomenon does not occur within tissues. The production of unopposed hyaluronidase activity would cause great havoc in tissues. Simultaneous deposition of hyaluronidases and their inhibitors is a reasonable scenario, one that parallels control of the matrix metalloproteinases by their TIMPs (tissue inhibitors of MMPs). 

Inhib. abbrev. DTT = dithioghreitol E64D = epoxysuccinyl-L-leucyl-amido-3-methyl-butane ethyl ester EDTA = ethylene-diamine-tetra-acetic acid EGTA = ethylen-glycol-tetra-acetic acid LHVS = morpholinurea-leucine-homophenyl-alanine-vinylsulfone-phenyl NEM = N-ethyl-maleimide PAI = plasminogen activator inhib. PMSF = phenil-methyl-sulfonil fluoride SBTl = soybean trypsin inhib. TIMP = tissue inhib. of metalloproteinases TPCK = tosyl-L-phenyl-alanyl-chloro-methane Al.so termed stephins. 

Benelh, R., Adatia, R., Ensoli, B., Stetler-Stevenson, W. G., Santi, L. and Al-bini, A. (1994). Inhibihon of AIDS-Kaposi s sarcoma ceU induced endothehal ceU invasion by TIMP-2 and a synthetic peptide from the metalloproteinase propeptide imphcations for an anti-angiogenic therapy. Oncol. Res. 6, 251-257. 

Stetler-Stevenson, W. G., Brown, P. D., Onisto, M., Levy, A. T. and Liotta, L. A. (1990). Tissue inhibitor of metalloproteinase-2 (TIMP-2). mRNA expression in tumor cell lines and human tumor tissues. J. Biol. Chem. 265,13933-13938. 

The functions of the extracellular matrix are manifold (1.) stabilization of the tissue and organ structure, (2.) structural linkage of cells, (3.) transmission of information between the various types of cells within the tissue and the extracellular milieu, (4.) adhesion or migration of cells, and (5.) influence on the development and differentiation of cells and their polarity. In fibrogenesis, collagen fibres build the framework in which the other components of the extracellular matrix are embedded. In line with this wide scop>e of functions, the extracellular matrix is not only organ-sp>ecific as regards its architecture, but it also displays variations at different locations within the liver, e.g. in Disse s space, in the periportal fields and within the acinus zones. The extracellular matrix is a dynamic structure, i. e. there is a constant equilibrium between build-up (by matrix-metalloproteinases = MMP) and break-down (by tissue inhibitors of matrix metaUoproteinases = TIMP). 

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