title: Expanding the Activity of Tissue Inhibitors of Metalloproteinase (TIMP)-1 against Surface-Anchored Metalloproteinases by the Replacement of Its C-Terminal Domain: Implications for Anti-Cancer Effects.
abstract: Tissue inhibitors of metalloproteinases (TIMPs) are the endogenous inhibitors of the matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs). TIMP molecules are made up of two domains: an N-terminal domain that associates with the catalytic cleft of the metalloproteinases (MP) and a smaller C-terminal domain whose role in MP association is still poorly understood. This work is aimed at investigating the role of the C-terminal domain in MP selectivity. In this study, we replaced the C-terminal domain of TIMP-1 with those of TIMP-2, -3 and -4 to create a series of "T1:TX" chimeras. The affinity of the chimeras against ADAM10, ADAM17, MMP14 and MMP19 was investigated. We can show that replacement of the C-terminal domain by those of other TIMPs dramatically increased the affinity of TIMP-1 for some MPs. Furthermore, the chimeras were able to suppress TNF-α and HB-EGF shedding in cell-based setting. Unlike TIMP-1, T1:TX chimeras had no growth-promoting activity. Instead, the chimeras were able to inhibit cell migration and development in several cancer cell lines. Our findings have broadened the prospect of TIMPs as cancer therapeutics. The approach could form the basis of a new strategy for future TIMP engineering.
authors: From the Department of Biological Sciences, Xian Jiaotong Liverpool University, 111 Ren Ai Road, Suzhou, China.
authors: Jing Xian
authors: JX
authors: Duan
authors: Department of Oncology, Cambridge University, Cancer Research Institute, Cambridge, United Kingdom.
authors: Magdalini
authors: M
authors: Rapti
authors: From the Department of Biological Sciences, Xian Jiaotong Liverpool University, 111 Ren Ai Road, Suzhou, China.
authors: Anastasia
authors: A
authors: Tsigkou
authors: From the Department of Biological Sciences, Xian Jiaotong Liverpool University, 111 Ren Ai Road, Suzhou, China.
authors: Meng Huee
authors: MH
authors: Lee
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D066257:Heparin-binding EGF-like Growth Factor / Q000737:chemistry; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D019714:Tissue Inhibitor of Metalloproteinases / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014945:Wound Healing / Q000187:drug effects
chemical_list: D066257:Heparin-binding EGF-like Growth Factor; D061965:Matrix Metalloproteinase Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D020782:Matrix Metalloproteinases