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A disintegrin and metalloproteinase with thrombospondin motifs 18 are abbreviated as ADAMTS18. ADAMTS18 is a member of the ADAMTS (disintegrin and metalloproteinase with thrombospondin motif) protein family. Members of the ADAMTS family share several different protein modules, including the propeptide region, the metalloproteinase domain, the disintegrin-like domain, and the thrombospondin type 1 (TS) motif.
It is most closely related to ADAMTS16, which has 57% overall identity and 85% identity. ADAMTS18 mRNA was found to be abundantly expressed in all normal human tissues. In human fetal tissues, ADAMTS18 mRNA expression was found in the lung, liver, and kidney. Endothelial cells constitutively express ADAMTS18. TNF-α induces secretion of ADAMTS18 in cultured ECs.
Like all ADAMTS, ADAMTS18 also has a furin cleavage site that releases mature proteins through the pre-cleavage domain. In addition, ADAMTS18 was cleaved between Arg775 and Ser776 in the spacer region by thrombin to release a C-terminal 45 kDa platelet active fragment comprising the five TSR domains and the PLAC domain at the ends. An N-glycosylated consensus sequence (NVT) was found in its catalytic domain. The strong expression of Adamts18 mRNA in the lens and retina during mouse embryonic development indicates the role of ADAMTS18 in eye development. After thrombin cleavage, ADAMTS18 causes oxidative platelet rupture and platelet-thromb degradation, suggesting that it may play a physiological role in hemostasis.
Figure 1. Interaction between thrombin and ADAMTS-18 in haemostatic balance. (Wei,. et al. 2014)
Wei et al. summarized the interaction of thrombin with ADAMTS-18 in hemostatic balance. Endothelial cells can express ADAMTS-18. Thrombin increases the expression of ADAMTS-18 with the ability to cleave it into 45KD and then activate the C-terminus. When Thrombin promotes platelet aggregation, the C-terminus of ADAMTS-18 is inhibited. Notably, the thrombin cleavage site is located in the spacer region between Arg775 and Ser776.
Data from Peluso et al. suggest that different mutations in ADAMTS18 can be linked to the pathogenesis of different eye diseases, helping to further elucidate the molecular mechanisms of hereditary retinal dystrophy complexity. The Chandra et al. report describes the detailed phenotype of four patients with new homozygous mutations in ADAMTS18. They believe that retinal dystrophy is a key feature of patients with ADAMTS18 mutations. A phenotypic overlap associated with the ADAMTS18 mutation and KNOBLCH syndrome, a rare autosomal recessive disorder associated with the COL18A1 gene mutation.
Preeclampsia is the result of impaired trophoblastic infiltration and spiral artery remodeling, and its etiology and pathophysiology are controlled by the inflammatory response. Eda et al. studied and compared serum molecules between pre-eclampsia and control groups, including IL-33, ADAMTS12, ADAMTS16 and ADAMTS18 levels, and studied the role of these molecules in pre-eclampsia. It was concluded that the expression level of ADAMTS18 in the serum of pre-eclampsia was not significantly different from that of the control group, and pre-eclampsia was considered to be associated with lower serum IL-33 and ADAMTS12 levels.
ADAMTS18 and Tumor
Schell et al. analyzed the polygenic mutations in 468 patients with rectal cancer. The results suggest that the mutation of ADAMTS18 is closely related to the occurrence of rectal cancer. And other studies have also pointed out that ADAMTS18 gene mutation is associated with the occurrence of renal cell carcinoma and colon cancer. In a mouse model, ADAMTS18 expression is down-regulated by β-catenin expression and activation of p38MAPK / ERK1 /2 signaling promotes colon carcinogenesis.
ADAMTS18 and Breast Cancer
Xu et al. found that ADAMTS18 is frequently down-regulated or silenced by promoter methylation in breast cancer cells and primary tissues. ADAMTS18 is methylated in 70.8% of primary breast cancer but not methylated in normal breast tissue, indicating tumor-specific methylation. Demethylation restored the expression of ADAMTS18 in breast cancer cells, suggesting that promoter methylation directly mediates its silencing. The data indicate that ectopic expression of ADAMTS18 inhibits migration and invasion of breast cancer cell lines by down-regulating Akt and NF-κB activity, but has no significant effect on cell proliferation. ADAMTS18 inhibits breast cancer metastasis in vivo. These results indicate that ADAMTS18 acts to inhibit tumors by inhibiting the migration and invasion of breast cancer.
ADAMTS18 and Melanoma
The invasive relationship between ADAMTS18 and melanoma ADAMTS18, also known as ADAMTS 21, HGNC: 16662, etc., is mainly expressed in the heart, skin, brain, and mammary muscle epithelial cells. The ADAMTS18 gene is located in the 16q23 region, which is the most susceptible region of the mutation. Its loss of heterozygosity is closely related to the occurrence of various cancers, so the ADAMTS18 gene is easily mutated. The ADAMTS18 gene often initiates methylation in a variety of tumors, such as esophageal cancer, nasopharyngeal carcinoma, liver cancer, breast cancer, and cervical cancer. This methylation is a driving mechanism for silencing the ADAMTS18 gene, so it is considered to be a novel tumor suppressor gene.
Wei et al. showed that ADAMTS18 gene is highly susceptible to the mutation in melanoma cells, and mutant ADAMTS18 can promote melanoma cell proliferation, migration, and metastasis. The ADAMTS18 product is similar to other members of the family and acts as a secreted protease secreted into ECM. Mutation of ADAMTS18 also affects its cellular localization, resulting in more secreted proteins of ADAMTS18 being retained on the cell surface rather than released into the ECM. At the same time, Wei et al. quantified shRNA by RT-PCR in the cell line knocking out the ADAMTS18 gene. The results showed that the mutated ADAMTS18 is a necessary factor for melanoma cell migration. Therefore, the mutated ADAMTS18 is considered to be a new "promoter" for melanoma development.
Which region of ADAMTS18 can exert tumor suppressive effects is currently unclear. However, a recent study found that its auxiliary area plays an important role in dissolving platelet emboli. The C-terminal helper region may inhibit metastasis by regulating platelet function or may dissolve tumor cell emboli and platelet emboli.