Vimentin takes part in functioning as one such stimulus for MT1-MMP activation [32]. thus causing metastasis. Despite the long-time efforts spent on the development of MT1-MMP interventions, none have been accomplished yet due to the side effects caused by off-target effects. Recently, MT1-MMP-specific small molecule inhibitors or an antibody have been reported and these inhibitors could potentially be novel brokers for cancer treatment. Keywords: MT1-MMP, cancer, metastasis, ECM 1. Introduction Matrix metalloproteinases (MMPs) are common proteinases composed of 23 members in humans, 6 of which were discovered as MMPs mTOR inhibitor (mTOR-IN-1) tethered to the plasma membrane, called membrane-type MMP (MT-MMP). Among MT-MMPs, MT1-MMP, also referred to Rabbit polyclonal to HSP27.HSP27 is a small heat shock protein that is regulated both transcriptionally and posttranslationally. as MMP-14, was the first MT-MMP to be identified [1] as a cell surface proteinase expressed in invasive mTOR inhibitor (mTOR-IN-1) tumors, followed by the discovery of MT2-MMP (MMP-15), MT3-MMP (MMP-16), MT4-MMP (MMP-17), MT5-MMP (MMP-24), and MT6-MMP (MMP-25). MT-MMPs are characterized as two subgroups, transmembrane (TM)-type and glycosylphosphatidylinositol (GPI)-type, which are tethered to TM and GPI, respectively. MT4-MMP and MT6-MMP are the GPI-type MMP and the rest of the MMPs are classified into TM-type. Although the functions of most of the MMPs are not well elucidated yet, MT1-MMP is the most well-characterized MMP in the aspect of its role in the invasion and metastasis of cancer cells, and even its non-proteolytic involvement in the indirect enhancement of hypoxia-inducible factor-1 alpha (HIF-1A) activity and the regulation of its endosomal trafficking. MT1-MMP is one of the collagenases and exhibits proteinase activities on extracellular matrix components, cell surface molecules, and certain types of cytosolic proteins. Now, MT1-MMP is known to be often associated with cancer metastasis in various mechanisms depending on the cell types. Regarding the extremely wide influence of MT1-MMP on various substrates and diseases, we would like to briefly summarize the involvement of MT1-MMP in cancer metastasis. 2. The Fundamentals of MT1-MMP 2.1. The Structure of MT1-MMP MMP families retain well-conserved domains within the extracellular region, which include signal peptide, pro-peptide, RXKR motif, and zinc-dependent catalytic motif within the N-terminal half; and the hemopexin-like (HPX) domain name with adjacent linkers within the C-terminal half. What differentiates the TM-type and GPI-type is the TM domain name with the adjacent cytoplasmic region, which comprises 20 amino acids, or the GPI signal domain name, which lacks the cytoplasmic region, around the C-terminal end of the MT-MMPs, respectively [2,3]. Additionally, only TM-type MMPs retain the insertion of 8C9 amino acids named MT-loop within its catalytic domain name [4,5]. MT1-MMP was the first MMP to be discovered as TM-type [1]. Although MT1-MMP is known as a cell surface protein, it initially localizes at the Golgi apparatus as an inactive state (pro-MMP) before it is transported to the cell surface and mTOR inhibitor (mTOR-IN-1) there, pro-MMP turns to the active state after receiving proteolytic processing between the RXKR motif and the catalytic domain name via furin [6]. The gene comprises 10 exons comparable to most of the other MMPs except for MMP-2 and MMP-13 which comprise 13 and 8 exons, respectively. However, the domain name coded with exon 2 in other MMPs is divided into two exons, exon 2 and 3, in MT1-MMP, and on the other hand, exon 3 and 4 in other MMPs converge on exon 4 only [7] (Physique 1). Open in a separate window Physique 1 Exon mapping of MMP proteins. An exon mapping of MT1-MMP as a representative membrane type MMP is usually described compared with the MMP-1 as an original MMP and MMP-2 as an MMP that has a core relationship with MT1-MMP. SP: signal peptide, Pro: pro-domain, CAT: catalytic domain name, HPX: HPX domain name, TM: transmembrane domain name, CPT: cytoplasmic tail, FN: fibronectin-like domain name, RXKR: RXKR motif. 2.2. How MT1-MMP Expressions Are Regulated MT1-MMP is usually expressed in various types of cells such as fibroblasts, osteoblasts, and epithelial cells [4]. Additionally, cancer cells exhibit higher levels of MT1-MMP expression, and that associates with poor prognosis [8,9,10,11,12]. Since the distributions and the substrates of MT1-MMP are extremely diverse, its expression is usually strictly controlled at an appropriate level depending on the situation through transcriptional and epigenetic regulations. For example, the expression of MT1-MMP is usually maintained at a high level during mouse embryogenesis in the developing urinary bladder, skeletal formation, muscular.
Vimentin takes part in functioning as one such stimulus for MT1-MMP activation [32]