TIMP3

What is TIMP3 protein?

TIMP3 (TIMP metallopeptidase inhibitor 3) gene is a protein coding gene which situated on the long arm of chromosome 22 at locus 22q12. TIMP3 is a unique member of the TIMP family due to its extracellular matrix (ECM)-binding property and its ability to inhibit a broad range of substrates, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAM with thrombospondin motifs (ADAMTSs). Besides its inhibitory function, TIMP3 can interact with proteins in the extracellular space, leading to various biological functions. TIMP3 mRNA contains a long 3' untranslated region (UTR), which is a target for numerous microRNAs. TIMP3 protein is consisted of 211 amino acids and its molecular mass is approximately 24.1 kDa.

What is the function of TIMP3 protein?

TIMP3 is unique among the TIMP family due to its extracellular matrix (ECM)-binding property and its ability to inhibit a broad range of substrates, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and ADAM with thrombospondin motifs (ADAMTSs). TIMP3 is involved in the regulation of processes such as cell proliferation, migration, differentiation, angiogenesis, and apoptosis. It can also degrade various extracellular matrix proteins, playing a crucial role in many physiological processes. TIMP3 can inhibit angiogenesis by interacting directly with the vascular endothelial growth factor (VEGF) receptor 2, thus suppressing the formation of new blood vessels. TIMP3 is also an inflammation factor inhibitor, negatively regulating TNF-alpha converting enzyme (TACE), which leads to increased release of TNF-alpha, a key inflammatory cytokine.

TIMP3 Related Signaling Pathway

TIMP3 is known for its ability to inhibit a broad spectrum of MMPs, which are enzymes responsible for the breakdown and remodeling of the extracellular matrix. In addition to MMPs, TIMP3 can also inhibit a disintegrin and metalloproteinases (ADAMs) as well as ADAM with thrombospondin motifs (ADAMTSs), which are involved in protein processing and matrix degradation. TIMP3 has anti-angiogenic properties and can inhibit the formation of new blood vessels by interacting with the vascular endothelial growth factor (VEGF) receptor 2, thus playing a role in the regulation of angiogenesis. TIMP3 is involved in the negative regulation of the TNF-alpha converting enzyme (TACE), which leads to a decrease in the release of TNF-alpha, a key inflammatory cytokine.

Fig1. Proposed mechanistic scheme: miR-29c suppresses breast cancer by the TIMP3/STAT1/FOXO1 pathway. (Wan Li, 2018)

TIMP3 Related Diseases

TIMP3 levels are found to be reduced in various cardiovascular diseases. Its replenishment has been shown to ameliorate the disease, indicating a potential therapeutic role for TIMP3 in cardiovascular conditions such as myocardial infarction and atherosclerosis. TIMP3's expression is associated with tumor progression. Its downregulation can lead to increased activity of proteases, promoting tumor growth and metastasis. TIMP3 is also suggested to be a potential therapeutic target for cancer treatment. TIMP3 is an inflammation factor inhibitor, negatively regulating TACE (TNF-alpha converting enzyme). TIMP3's expression has been linked to diabetic eye diseases, suggesting it could be a potential target for treatment.

Bioapplications of TIMP3

Due to the potential therapeutic effect of TIMP3 in cardiovascular diseases, recombinant TIMP3 protein can be used to treat cardiovascular diseases such as myocardial infarction and atherosclerosis. Supplementation with TIMP3 can help stabilize plaque and reduce myocardial remodeling and ventricular remodeling. TIMP3 plays a role in tissue repair and regeneration, and the recombinant TIMP3 protein may be used to promote wound healing and tissue regeneration.

Case Study 1: Viviana Casagrande, 2021

Diabetic nephropathy (DN), one of the major complications of diabetes, is characterized by albuminuria, glomerulosclerosis, and progressive loss of renal function. Loss of TIMP3, an Extracellular Matrix bound protein affecting both inflammation and fibrosis, is a hallmark of DN in human subjects and mouse models. This study was designed to provide evidences that the modulation of the system involving TIMP3 and its target A Disintegrin And Metalloproteinase 17 (ADAM17), may rescue kidney pathology in diabetic mice. DBA/2J mice were administered new peptides based on the human TIMP3 N-terminal domain, specifically conjugated with G3C12, a carrier peptide highly selective and efficient for transport to the kidney. Twelve weeks after Streptozotocin injections, 24-hour albuminuria was determined by ELISA, kidney morphometry was analyzed by periodic acid-shift staining, and Real Time-PCR and western blot analysis were performed on mRNA and protein extracted from kidney cortex. The results showed that both genetic modifications and peptides treatment positively affect renal function and structure in diabetic mice, as indicated by a significant and consistent decline in albuminuria along with reduction in glomerular lesions, as indicated by reduced mesangial expansion and glomerular hypertrophy, decreased deposition of extracellular matrix in the mesangium, diminished protein expression of the NADPH oxidases 4 (NOX4).

Fig1. Inhibition of human MMP2, MMP9, and ADAM17 enzyme activity.

Fig2. Protein expression in kidney cortex.

Case Study 2: Sunyoung Park, 2019

The human skin is the outermost physical barrier and has its own circadian machinery that works either cooperatively with the central clock, or autonomously. Circadian rhythms have been observed in many functions related to epidermal homeostasis including hydration and inflammation, and this functional oscillation is disturbed by ultraviolet radiation (UVR), which is a strong environmental cue. Among the genes estimated to show circadian expression in the skin, metalloproteinase inhibitor 3 (TIMP3), has a rhythmic expression in synchronized human keratinocytes similar to that of the core clock gene PER1 and an epidermal circadian regulatory gene, aquaporin 3 (AQP3) but was antiphase to the core clock gene BMAL1. Tumor necrosis factor-α (TNF-α), the regulatory target of TIMP3 via a disintegrin and metalloproteinase domain 17 (ADAM17), was inversely regulated when TIMP3 expression was downregulated by ultraviolet B (UVB) treatment. When synthetic TIMP3 peptides were applied to the cells, the secretion of TNF-α did not increase following the UVB treatment. Similar to TIMP3 peptides, Camellia sinensis leaf-derived extracts showed a distinguishing efficacy in recovering TIMP3 expression, downregulated by UVB treatment.

Fig3. The secreted or cytosolic TIMP3 and aquaporin 3 (AQP3) were examined at ZT 8 and 24 after UVB irradiation.

Fig4. NHEKs were irradiated following each scheme and harvested every 4 h.

TIMP3 has several biochemical functions, for example, metal ion binding,metalloendopeptidase inhibitor activity,protease binding. Some of the functions are cooperated with other proteins, some of the functions could acted by TIMP3 itself. We selected most functions TIMP3 had, and list some proteins which have the same functions with TIMP3. You can find most of the proteins on our site.

TIMP3 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with TIMP3 here. Most of them are supplied by our site. Hope this information will be useful for your research of TIMP3.

AGTR2;ADAMTS5