Regulation of MT1-MMP Activation and Its Relevance to Disease Processes
Matrix metalloproteases (MMPs) are members of zinc-dependent enzymes involved in the degradation of extracellular matrix (ECM) components. Among these enzymes, membrane-type 1 MMP (MT1-MMP) has been established as a vital enzyme in pericellular proteolysi
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Abstract Matrix metalloproteases (MMPs) are members of zinc-dependent enzymes involved in the degradation of extracellular matrix (ECM) components. Among these enzymes, membrane-type 1 MMP (MT1-MMP) has been established as a vital enzyme in pericellular proteolysis of the ECM macromolecules and shown to be involved in regulating different cellular and tissue characteristics and function in normal and pathological conditions. The enzyme is also important for skeletal development, cancer invasion, growth, neovessel formation, cell invasion as well as various signal transduction events. In this review, we summarize some information about regulation of MT1-MMP expression and activity and the recent knowledge of participation of MT1-MMP in different physiological and pathological events. Keywords Extracellular matrix • Matrix metalloprotease • Membrane type1 matrix metalloprotease • Signal transduction • Angiogenesis
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Introduction
Proteases are important in various physiological and pathological processes. Based on the preference of cleavage of peptide bond in substrates, they can be classified as exopeptidase (terminal peptide bond) or endopeptidase (internal peptide bond). Most endopeptidases are classified as serine, cysteine, aspartic or metalloproteases based on their catalytic mechanism and inhibitor sensitivities. Matrix metalloproteases (MMP) are multifunctional zinc-dependent endopeptidases that can degrade a variety of extracellular matrix (ECM) components, like collagens, laminin,
S. Roy • T. Chakraborti (*) • A. Chowdhury • K. Dey • S. Chakraborti Department of Biochemistry and Biophysics, University of Kalyani, Kalyani 741235, West Bengal, India e-mail: [email protected]; [email protected] S. Chakraborti and N.S. Dhalla (eds.), Proteases in Health and Disease, Advances in Biochemistry in Health and Disease 7, DOI 10.1007/978-1-4614-9233-7_12, © Springer Science+Business Media New York 2013
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Cat
L1
Hpx
L2 TM Cyt COOH2
Fig. 1 Domain arrangements of MT1-MMP. MT1-MMP is synthesized with a signal peptide (Sig) for its trafficking to membrane, a prodomian (Pro) for its latency, a catalytic domain (Cat) with catalytic zinc atom (Zn) for proteolytic activity, a hinge region (L1, linker 1) which provides better flexibility of catalytic and Hpx domains, a hemopexin domain (Hpx) which interacts with cell surface molecules like CD44 and homodimer formation, a stalk (L2, linker 2) region, a type-1 transmembrane domain (TM), and a cytoplasmic tail (Cyt), important for clathrin-mediated internalization of MT1-MMP, recycling and palmitoylation
fibronectin, vitronectin, aggrecan, enactin, versican, perlecan, tenascin and elastin [1]. The MMP family of enzymes consists of 24 zinc-dependent endopeptidases in humans. MMPs are secreted as soluble or membrane type-MMPs (MT-MMPs), which are anchored to the cell surface through transmembrane domain or glycosylphosphatidylinositol (GPI) linker. MT-MMPs are type 1 transmembrane proteins with a single membrane spanning
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