The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity

Over the past 20 years, the tissue inhibitors of metalloproteinases (TIMPs) have been implicated in direct regulation of cell growth and apoptosis. However, the mechanisms of these effects have been controversial. Recent work by several laboratories has identified specific signaling pathways and cell surface binding partners for members of the TIMP family. TIMP-2 binding to the integrin alpha(3)beta(1) is the first description of a cell surface receptor for a TIMP family member. TIMP-2 has been shown to induce gene expression, to promote G(1) cell cycle arrest, and to inhibit cell migration. TIMP-1 binding to CD63 inhibits cell growth and apoptosis. These new findings suggest that TIMPs are multifunctional and can act either directly through cell surface receptors or indirectly through modulation of protease activity to direct cell fate. The emerging concept is that TIMPs function in a contextual fashion so that the mechanism of action depends on the tissue microenvironment.

/pdf/tissue-inhibitors-of-metalloproteinases-in-cell-signaling-27s0ywbuae.pdf

Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities.

The activity of matrix metalloproteinases (MMPs) is regulated at several levels, including enzyme activation, inhibition, complex formation and compartmentalization. Regulation at the transcriptional level is also important, although this is not a subject of the present minireview. Most MMPs are secreted and have their function in the extracellular environment. This is also the case for the membrane-type MMPs (MT-MMPs). MMPs are also found inside cells, both in the nucleus, cytosol and organelles. The role of intracellular located MMPs is still poorly understood, although recent studies have unraveled some of their functions. The localization, activation and activity of MMPs are regulated by their interactions with other proteins, proteoglycan core proteins and/or their glycosaminoglycan chains, as well as other molecules. Complexes formed between MMPs and various molecules may also include interactions with noncatalytic sites. Such exosites are regions involved in substrate processing, localized outside the active site, and are potential binding sites of specific MMP inhibitors. Knowledge about regulation of MMP activity is essential for understanding various physiological processes and pathogenesis of diseases, as well as for the development of new MMP targeting drugs.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1742-4658.2010.07920.x

Regulation of matrix metalloproteinase activity in health and disease

Matrix metalloproteinases (MMPs) are a family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases that have the capacity to degrade almost every component of the ECM. The degradation of the ECM is of great importance, since it is related to embryonic development and angiogenesis. It is also involved in cell repair and the remodeling of tissues. When the expression of MMPs is altered, it can generate the abnormal degradation of the ECM. This is the initial cause of the development of chronic degenerative diseases and vascular complications generated by diabetes. In addition, this process has an association with neurodegeneration and cancer progression. Within the ECM, the tissue inhibitors of MMPs (TIMPs) inhibit the proteolytic activity of MMPs. TIMPs are important regulators of ECM turnover, tissue remodeling, and cellular behavior. Therefore, TIMPs (similar to MMPs) modulate angiogenesis, cell proliferation, and apoptosis. An interruption in the balance between MMPs and TIMPs has been implicated in the pathophysiology and progression of several diseases. This review focuses on the participation of both MMPs (e.g., MMP-2 and MMP-9) and TIMPs (e.g., TIMP-1 and TIMP-3) in physiological processes and on how their abnormal regulation is associated with human diseases. The inclusion of current strategies and mechanisms of MMP inhibition in the development of new therapies targeting MMPs was also considered.

https://www.mdpi.com/1422-0067/21/24/9739/pdf

The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases.

The ability of carcinoma cells arising at primary sites to cross their underlying basement membrane (BM), a specialized form of extracellular matrix that subtends all epithelial cells, and to access the host vasculature are central features of the malignant phenotype. The initiation of the invasive phenotype has been linked to the aberrant expression of zinc-finger transcriptional repressors, like Snail1, which act by triggering an epithelial-mesenchymal cell-like transformation (EMT-like) via the regulation of largely undefined, downstream effectors. Herein, we find that Snail1 induces cancer cells to (i) degrade and perforate BM barriers, (ii) initiate angiogenesis, and (iii) and intravasate vascular networks in vivo via a matrix metalloproteinase (MMP)-dependent process. Unexpectedly, the complete Snail1 invasion program can be recapitulated by expressing directly either of the membrane-anchored metalloproteinases, MT1-MMP or MT2-MMP. The pro-invasive, angiogenic, and metastatic activities of MT1-MMP and MT2-MMP are unique relative to all other metalloproteinase family members and cannot be mimicked in vivo by the secreted MMPs, MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, or MMP-13. Further, siRNA-specific silencing of MT1-MMP and MT2-MMP ablates completely the ability of Snail1 to drive cancer cell BM invasion, induce angiogenesis, or trigger intravasation. Taken together, these data demonstrate that MT1-MMP and MT2-MMP cooperatively function as direct-acting, pro-invasive factors that confer Snail1-triggered cells with the key activities most frequently linked to morbidity and mortality in cancer.

https://www.pnas.org/content/pnas/106/48/20318.full.pdf

Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1

https://dspace.ewha.ac.kr/bitstream/2015.oak/229141/1/Substrate%20cleavage%20analysis%20of%20furin%20and%20related%20proprotein%20convertases%20A%20comparative%20study.pdf

Substrate cleavage analysis of furin and related proprotein convertases: A comparative study

Tissue inhibitor of metalloproteinases-2 binding to membrane-type 1 matrix metalloproteinase induces MAPK activation and cell growth by a non-proteolytic mechanism.

Eok Soo Oh

Papers

Substrate cleavage analysis of furin and related proprotein convertases: A comparative study

Tissue inhibitor of metalloproteinases-2 binding to membrane-type 1 matrix metalloproteinase induces MAPK activation and cell growth by a non-proteolytic mechanism.