title: Expression level and glycan dynamics determine the net effects of TIMP-1 on cancer progression.
abstract: Tissue inhibitor of metalloproteinases (TIMPs; TIMP-1, -2, -3 and -4) are endogenous inhibitor for matrix metalloproteinases (MMPs) that are responsible for remodeling the extracellular matrix (ECM) and involved in migration, invasion and metastasis of tumor cells. Unlike under normal conditions, the imbalance between MMPs and TIMPs is associated with various diseased states. Among TIMPs, TIMP-1, a 184-residue protein, is the only N-linked glycoprotein with glycosylation sites at N30 and N78. The structural analysis of the catalytic domain of human stromelysin-1 (MMP-3) and human TIMP-1 suggests new possibilities of the role of TIMP-1 glycan moieties as a tuner for the proteolytic activities by MMPs. Because the TIMP-1 glycosylation participate in the interaction, aberrant glycosylation of TIMP-1 presumably affects the interaction, thereby leading to pathogenic dysfunction in cancer cells. TIMP-1 has not only the cell proliferation activities but also anti-oncogenic properties. Cancer cells appear to utilize these bilateral aspects of TIMP-1 for cancer progression; an elevated TIMP-1 level exerts to cancer development via MMP-independent pathway during the early phase of tumor formation, whereas it is the aberrant glycosylation of TIMP-1 that overcome the high anti-proteolytic burden. The aberrant glycosylation of TIMP-1 can thus be used as staging and/or prognostic biomarker in colon cancer.
authors.affiliation: Division of KRIBB Strategy Projects, KRIBB, Yuseong-gu, Deajeon, Korea.
authors.forename: Yong-Sam
authors.initials: YS
authors.lastname: Kim
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Jeong-Gu
authors.initials: JG
authors.lastname: Kang
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Ko
mesh_terms: D000818:Animals; D018450:Disease Progression; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011134:Polysaccharides / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
chemical_list: D011134:Polysaccharides; D019715:Tissue Inhibitor of Metalloproteinase-1; D020782:Matrix Metalloproteinases