The regulation of transmembrane metalloproteinases and their functions
Date
2018
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Publisher
University of Delaware
Abstract
Members of the metzincin superfamily of metalloproteinases, including the disintegrin and metalloproteinases (ADAMs) and the matrix metalloproteinases (MMPs), have long been associated with diseases such as cancer and arthritis. Among all the metzincin metalloproteinases, transmembrane metzincins such as transmembrane ADAMs and transmembrane MMPs, have emerged as new targets for cancer therapy. ☐ Previous research in our lab suggests that ADAM9, which is highly expressed in many types of solid tumors, promotes colorectal cancer (CRC) progression. To understand the mechanism of action for ADAM9, I carried out RNA-seq in HCT116 human CRC cells with ADAM9 knockdown. A total of 351 differentially expressed genes (DEGs), including 93 up-regulated genes and 258 down-regulated genes, were identified. My enrichment analysis revealed that MAPK signaling pathway, p53 signaling pathway and FoxO signaling pathway, are significantly enriched. These pathways may mediate the function of ADAM9 in CRC progression. ☐ My bioinformatics analysis predicts the C-terminal lysine residue in the cytoplasmic tail of several ADAMs may be ubiquitinated to target these ADAMs for proteasome-mediated degradation. One of these ADAMs, ADAM12, has been implicated in the pathology of malignant tumors, such as breast cancer. To test if the C-terminal K903 residue is important for ADAM12 turnover, I generated the K903R mutant, as well as a mutant with the whole cytoplasmic tail deleted. I found that the levels of both mutants are elevated as compared with wild-type ADAM12. My findings indicate that the most C-terminal lysine residue of ADAM12 is likely involved in its degradation. ☐ The third part of this research concerns a cross-regulation of transmembrane metalloproteinases by cysteine proteases. We found that treatment of both normal and neuroblastoma cells with K777, a cysteine protease inhibitor, leads to post-transcriptional accumulation of MMP14. Surprisingly, MMP14 substrates also accumulate in the cells, suggesting that the activity of this transmembrane MMP is actually inhibited. We therefore hypothesize that the accumulation of MMP14 upon K777 treatment is due to reduced autocleavage. Consistent with this hypothesis, a protease-dead mutant of MMP14 does not accumulate after K777 treatment. These results unveil a possible crosstalk between cysteine proteases and transmembrane metalloproteinases, which warrants further investigation.
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Biological sciences