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

By K. Brew, Hideaki Nagase. Biochimica et Biophysica Acta, 2010

1,318 citations recorded by the source corpus.

Tissue inhibitors of metalloproteinases (TIMPs) are widely distributed in the animal kingdom and the human genome contains four paralogous genes encoding TIMPs 1 to 4. TIMPs were originally characterized as inhibitors of matrix metalloproteinases (MMPs), but their range of activities has now been found to be broader as it includes the inhibition of several of the disintegrin-metalloproteinases, ADAMs and ADAMTSs. TIMPs are therefore key regulators of the metalloproteinases that degrade the extracellular matrix and shed cell surface molecules. Structural studies of TIMP–MMP complexes have elucidated the inhibition mechanism of TIMPs and the multiple sites through which they interact with target enzymes, allowing the generation of TIMP variants that selectively inhibit different groups of metalloproteinases. Engineering such variants is complicated by the fact that TIMPs can undergo changes in molecular dynamics induced by their interactions with proteases. TIMPs also have biological activities that are independent of metalloproteinases; these include effects on cell growth and differentiation, cell migration, anti-angiogenesis, anti- and pro-apoptosis, and synaptic plasticity. Receptors responsible for some of these activities have been identified and their signaling pathways have been investigated. A series of studies using mice with specific TIMP gene deletions has illuminated the importance of these molecules in biology and pathology.

Subfields: Cancer Research, Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/87010c1e57145a7e78794592015ac437df17462a

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Citations in the corpus

Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. (2011, background): “In addition, there are a family of inhibitors of MMPs, including TIMPs that regulate the activity of the active enzyme (Brew & Nagase 2010).”
Matrix MetalloProteinases (MMPs) andTissue Inhibitors of MetalloProteinases (TIMPs): positive and negative regulators intumor cell adhesion (2010, neutral): “Studies have revealed that TIMPs are involved in several biological activities including cell differentiation, growth, migration, invasion, angiogenesis and apoptosis, and these cellular effects are mediated independently of TIMP inhibition of MMP activity(reviewed in [94]) and Figure 2.”
Matrix metalloproteinase-9: Many shades of function in cardiovascular disease. (2013, background): “All TIMPs are known to interact with MMP-9 and inhibit its activity (9).”
Role of Matrix Metalloproteinases in Angiogenesis and Cancer (2019, background): “For further details about the structure and function of MMPs see (14, 15, 30).”
Extracellular Matrix Degradation and Remodeling in Development and Disease (2011, background): “…structurally and functionally distinct domains: an amino-terminal domain of about 125 amino acid residues, where much of the MMP inhibitor activity resides, and a carboxy-terminal domain of around 65 residues, which promotes binding between TIMPs and MMPs (Olson et al. 1997; Brew and Nagase 2010).”
The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases (2020, background): “TIMP-3 is unique among TIMPs, because it retains its ability to inhibit shedding enzymes, such as ADAM17, which are involved in inflammatory processes.”
Matrix metalloproteinases. (2010, background): “A recent special issue devoted to these proteins was published in Biochimica et Biophysica Acta [60,152,198-204].”
Tissue inhibitors of metalloproteinases (2011, background): “TIMP3 can be sequestered in the extracellular matrix in some tissues, but secreted TIMP3 can be rapidly endo cytosed by cells such as chondrocytes through a mechanism that involves the LDL-receptor-related protein (LRP) [6,21].”
A Disintegrin and Metalloprotease (ADAM): Historical Overview of Their Functions (2016, background): “Apart from being active towards matrix metalloproteinase, TIMP (tissue inhibitors of metalloproteinases) were shown to be active towards ADAMs [74].”