Research Topics
Genomes and GenesSpecies | Hideaki NagaseSummaryAffiliation: Imperial College Country: UK Publications
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Publications
Structure and function of matrix metalloproteinases and TIMPsHideaki Nagase
Department of Matrix Biology, Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1 Aspenlea Road, London W6 8LH, UK
Cardiovasc Res 69:562-73. 2006..This review introduces the members of the MMP family and discusses their domain structure and function, proenyme activation, the mechanism of inhibition by TIMPs and their significance in physiology and pathology...- Aggrecanases and cartilage matrix degradationHideaki Nagase
The Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London, UK
Arthritis Res Ther 5:94-103. 2003.... - Elucidating the function of non catalytic domains of collagenases and aggrecanasesHideaki Nagase
Matrix Biology Department, Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London, United Kingdom
Connect Tissue Res 49:169-74. 2008..Such molecules will be attractive for therapy as they will be highly selective because they are based on the unique mechanism of each proteinase... - Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4Christi Gendron
Kennedy Institute of Rheumatology Division, Imperial College London, London W6 8LH, United Kingdom
J Biol Chem 282:18294-306. 2007..Our studies suggest that ADAMTS-5 is a major aggrecanase in cartilage metabolism and pathology... - TIMP-3 inhibits aggrecanase-mediated glycosaminoglycan release from cartilage explants stimulated by catabolic factorsChristi Gendron
Kennedy Institute of Rheumatology Division, Imperial College London, 1 Aspenlea Road, W6 8LH, London, UK
FEBS Lett 555:431-6. 2003..Little apoptosis of primary porcine chondrocytes is observed at an effective concentration of N-TIMP-3. These results suggest that TIMP-3 may be a candidate agent for use against cartilage degradation... - The C-terminal domains of ADAMTS-4 and ADAMTS-5 promote association with N-TIMP-3Linda Troeberg
Kennedy Institute of Rheumatology, Imperial College London, Hammersmith, London, W6 8LH, UK
Matrix Biol 28:463-9. 2009..5-fold better K(i) value for full-length ADAMTS-5 than for the catalytic and disintegrin domain alone. We propose that the C-terminal domains of the enzymes affect the structure around the active site, favouring interaction with TIMP-3... - Functional differences of the catalytic and non-catalytic domains in human ADAMTS-4 and ADAMTS-5 in aggrecanolytic activityKazunari Fushimi
Kennedy Institute of Rheumatology Division, Imperial College London, 1 Aspenlea Road, Hammersmith, London W6 8LH, United Kingdom
J Biol Chem 283:6706-16. 2008..However, removal of the spacer domain from ADAMTS-4 greatly enhanced more general proteolytic activity against non-aggrecan substrates, e.g. E. coli-expressed interglobular domain, fibromodulin, and carboxymethylated transferrin... - The second dimer interface of MT1-MMP, the transmembrane domain, is essential for ProMMP-2 activation on the cell surfaceYoshifumi Itoh
Department of Matrix Biology, Imperial College London, Hammersmith, London W6 8LH, UK
J Biol Chem 283:13053-62. 2008..Our finding provides new insight into the potential molecular arrangement of MT1-MMP contributing to its function on the cell surface... - Reactive-site mutants of N-TIMP-3 that selectively inhibit ADAMTS-4 and ADAMTS-5: biological and structural implicationsNgee H Lim
Kennedy Institute of Rheumatology Division, Imperial College London, 65 Aspenlea Road, London W6 8LH, UK
Biochem J 431:113-22. 2010..These observations suggest that further mutation of the residues of N-TIMP-3 which make unique contacts with these metalloproteinases may allow discrimination between them... - Altered proteolytic activities of ADAMTS-4 expressed by C-terminal processingMasahide Kashiwagi
Kennedy Institute of Rheumatology Division, Imperial College London, United Kingdom
J Biol Chem 279:10109-19. 2004..Finding of ADAMTS-4 in the interleukin-1alpha-treated porcine articular cartilage primarily as a 46-kDa form suggests that it exhibits a broader substrate spectrum in the tissue than originally considered... - Membrane type 1 matrix metalloproteinase is a crucial promoter of synovial invasion in human rheumatoid arthritisMary Clare Miller
Imperial College London, London, UK
Arthritis Rheum 60:686-97. 2009..The aim of this study was to explore the role of one of the collagen-degrading matrix metalloproteinases (MMPs), membrane type 1 MMP (MT1-MMP), in synovial pannus invasiveness... - Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanasesLinda Troeberg
Kennedy Institute of Rheumatology Division, Imperial College London, 65 Aspenlea Rd, Hammersmith, London, W6 8LH, UK
FASEB J 22:3515-24. 2008..Studies with TIMP-3-null mouse cartilage indicated that CaPPS inhibition of aggrecan degradation is TIMP-3 dependent. These unique properties make CaPPS a prototypic disease-modifying agent for osteoarthritis... - Cell surface collagenolysis requires homodimerization of the membrane-bound collagenase MT1-MMPYoshifumi Itoh
Department of Matrix Biology, Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London W6 8LH, United Kingdom
Mol Biol Cell 17:5390-9. 2006..Our results introduce a new concept in that pericellular collagenolysis is regulated by correct molecular assembly of the membrane-anchored collagenase, thereby governing the directionality of the cell to migrate in tissue... - Collagenase unwinds triple-helical collagen prior to peptide bond hydrolysisLinda Chung
Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London, UK
EMBO J 23:3020-30. 2004..Our results throw light on the basic mechanisms that control a wide range of biological and pathological processes associated with tissue remodelling... - Dimerization of MT1-MMP during cellular invasion detected by fluorescence resonance energy transferYoshifumi Itoh
The Kennedy Institute of Rheumatology, Imperial College London, London W6 8LH, U K
Biochem J 440:319-26. 2011..Our data indicate that cell-surface collagenolytic activity is regulated co-ordinately with cell migration events to enable penetration of the matrix physical barrier... - Zymography of metalloproteinasesLinda Troeberg
Imperial College London, London, United Kingdom
Curr Protoc Protein Sci . 2004..This unit presents a representative zymography protocol for the study of matrix metallopeptidases (MMPs)... - Monitoring metalloproteinase activity using synthetic fluorogenic substratesLinda Troeberg
Imperial College London, London, United Kingdom
Curr Protoc Protein Sci . 2004..Other fluorogenic peptides and protein substrates, together with non-fluorogenic alternatives, are also discussed... - Palmitoylation at Cys574 is essential for MT1-MMP to promote cell migrationNarayanapanicker Anilkumar
Department of Matrix Biology, Kennedy Institute of Rheumatology Division, Imperial College London, London, UK
FASEB J 19:1326-8. 2005..Taken together, palmitoylation of MT1-MMP is one of the key posttranslational modifications that determines MT1-MMP-dependent cell migration... - Measurement of matrix metalloproteinase activities in the medium of cultured synoviocytes using zymographyLinda Troeberg
Imperial College, London, UK
Methods Mol Biol 225:77-87. 2003 - Connective tissue remodeling: cross-talk between endothelins and matrix metalloproteinasesDavid Abraham
Centre for Rheumatology and Connective Tissue Diseases, Department of Medicine, Royal Free and University College Medical School, London, UK
Curr Vasc Pharmacol 3:369-79. 2005..In this review we present the cross-talk between the endothelins and the MMP-TIMP system and their implications in controlling the normal and abnormal tissue remodeling... - Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistryRobert Visse
Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1 Aspenlea Rd, London W6 8LH, UK
Circ Res 92:827-39. 2003.... - Report on the Molecular Approaches to Osteoarthritis Symposium, Imperial College London, UK, 18-20 April 2004Jeremy Saklatvala
Kennedy Institute of Rheumatology, Imperial College Faculty of Medicine, London, UK
Arthritis Res Ther 6:203-7. 2004 - E. coli expression of TIMP-4 and comparative kinetic studies with TIMP-1 and TIMP-2: insights into the interactions of TIMPs and matrix metalloproteinase 2 (gelatinase A)Linda Troeberg
Kennedy Institute of Rheumatology Division, Imperial College of Science, Technology and Medicine, 1 Aspenlea Road, Hammersmith, London, W6 8LH UK
Biochemistry 41:15025-35. 2002..Similar models of interaction may apply to TIMP-4. The latter low-affinity site functions in conjunction with the active site of MMP-2 to generate a tight enzyme-inhibitor complex... - Shear stress-induced shedding of soluble intercellular adhesion molecule-1 from saphenous vein endotheliumSabena Sultan
Department of Vascular Surgery Charing Cross site, Imperial College London, St Dunstan s Road, London W6 8RP, UK
FEBS Lett 564:161-5. 2004..sICAM-1 was processed distal to Arg441, indicating that MMP-9, docking to ICAM-1, contributes to sICAM-1 shedding and attenuation of the shear stress-induced upregulation of ICAM-1... - Matrix metalloproteinases in cancerYoshifumi Itoh
Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, 1 Aspenlea Road, Hammersmith, London W6 8LH, U K
Essays Biochem 38:21-36. 2002..This review highlights recent developments with regard to the cellular and molecular mechanisms of MMPs that influence tumour cell growth, invasion and metastasis... - Engineering of tissue inhibitor of metalloproteinases mutants as potential therapeuticsHideaki Nagase
The Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK
Arthritis Res 4:S51-61. 2002..A potential therapeutic use of TIMP variants is discussed... - Catalytic properties of ADAM12 and its domain deletion mutantsJonas Jacobsen
Department of Biomedical Sciences and Biotech Research and Innovation Centre BRIC, University of Copenhagen, Ole Maaløes Vej 5, DK 2200 Copenhagen, Denmark
Biochemistry 47:537-47. 2008..These results indicate unique enzymatic properties of ADAM12 among the members of the ADAM family of metalloproteinases... - Crystal structure of an active form of human MMP-1Shalini Iyer
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
J Mol Biol 362:78-88. 2006..Comparing this structure with the human proMMP-1 shows significant structural differences, mainly in the relative orientation of the hemopexin domain, between the pro form and active form of the human enzyme... - Reappraising metalloproteinases in rheumatoid arthritis and osteoarthritis: destruction or repair?Gillian Murphy
Cancer Cell Biology, Department of Oncology, University of Cambridge, Cambridge, UK
Nat Clin Pract Rheumatol 4:128-35. 2008..Work on the development of effective biomarkers is also essential before an effective evaluation of the new generations of specific inhibitors can be made... - TIMP-3 inhibits the procollagen N-proteinase ADAMTS-2Wei Man Wang
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA
Biochem J 398:515-9. 2006..In contrast, TIMP-3 is demonstrated to inhibit ADAMTS-2 in vitro with apparent Ki values of 160 and 602 nM, in the presence of heparin or without respectively; and TIMP-3 is shown to inhibit procollagen processing by cells... - Individual Timp deficiencies differentially impact pro-MMP-2 activationJane L English
Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada
J Biol Chem 281:10337-46. 2006..Thus, TIMP-3 provides an inherent regulation over the kinetics of pro-MMP-2 processing, serving at a level distinct from that of TIMP-2 and TIMP-4... - Activation of membrane-type matrix metalloproteinase 3 zymogen by the proprotein convertase furin in the trans-Golgi networkTiebang Kang
Department of Pharmacology, University of Minnesota, 321 Church Street S.E, 6-120 Jackson Hall, Minneapolis, MN 55455, USA
Cancer Res 62:675-81. 2002..Thus, furin processes MT3-MMP zymogen in the trans-Golgi network, where they colocalize independently of their apparent enzyme-substrate relationship... - Protein engineering of the tissue inhibitor of metalloproteinase 1 (TIMP-1) inhibitory domain. In search of selective matrix metalloproteinase inhibitorsShuo Wei
Department of Biomedical Sciences, Florida Atlantic University, Boca Raton, Florida 33431, USA
J Biol Chem 278:9831-4. 2003..These selective TIMP variants may provide useful tools for investigation of biological roles of specific MMPs and for possible therapy of MMP-related diseases... - Differential inhibition of membrane type 3 (MT3)-matrix metalloproteinase (MMP) and MT1-MMP by tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-3 rgulates pro-MMP-2 activationHuiren Zhao
Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA
J Biol Chem 279:8592-601. 2004..These results demonstrate that TIMP-3 is a major regulator of MT3-MMP activity and further underscores the unique interactions of TIMPs with MT-MMPs in the control of pericellular proteolysis... - Matrix metalloproteinase triple-helical peptidase activities are differentially regulated by substrate stabilityDmitriy Minond
Department of Chemistry and Biochemistry, Florida Atlantic University, 777 Glades Road, Boca Raton, Florida 33431 0991, USA
Biochemistry 43:11474-81. 2004..These results demonstrate that collagenolytic MMPs have subtle differences in their abilities to hydrolyze triple helices and may explain the relative collagen specificity of MMP-1... - Low density lipoprotein receptor-related protein mediates endocytic clearance of pro-MMP-2.TIMP-2 complex through a thrombospondin-independent mechanismHerve Emonard
CNRS UMR 6198, IFR 53 Biomolecules, Faculty of Medicine, F 51100 Reims, France
J Biol Chem 279:54944-51. 2004..TIMP-2 complex is a TSP-independent two-step process, involving (i) initial binding to the cell membrane in a RAP-insensitive manner and (ii) subsequent LRP-dependent (RAP-sensitive) internalization and degradation... - Reactive site mutations in tissue inhibitor of metalloproteinase-3 disrupt inhibition of matrix metalloproteinases but not tumor necrosis factor-alpha-converting enzymeShuo Wei
Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida 33431, USA
J Biol Chem 280:32877-82. 2005.... - Matrix metalloproteinase expression and function during fin regeneration in zebrafish: analysis of MT1-MMP, MMP2 and TIMP2Shan Bai
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
Matrix Biol 24:247-60. 2005..Taken together, these results indicate that MMPs have an important role during fin regeneration in zebrafish... - Identification of a novel 82 kDa proMMP-9 species associated with the surface of leukaemic cells: (auto-)catalytic activation and resistance to inhibition by TIMP-1Christian Ries
Division of Clinical Chemistry and Clinical Biochemistry in the Surgical Department, Ludwig Maximilians University of Munich, 80336 Munich, Germany
Biochem J 405:547-58. 2007..Thus, the 82 kDa proMMP-9 expressed on the surface of malignant cells may escape inhibition by natural TIMP-1, thereby facilitating cellular invasion in vivo... - Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosisFrank R Murphy
Liver Group, Division of Infection, Inflammation and Repair, University of Southampton, Hampshire SO16 6YD, United Kingdom
J Biol Chem 277:11069-76. 2002..We conclude that TIMP-1 inhibits apoptosis of activated HSC via MMP inhibition... - Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptorsMatti Ahonen
Centre for Biotechonology, University of Turku, Finland
Oncogene 22:2121-34. 2003..Taken together, these results show that TIMP-3 promotes apoptosis in melanoma cells through stabilization of three distinct death receptors and activation of their apoptotic signaling cascade through caspase-8... - The expression of novel membrane-type matrix metalloproteinase isoforms is required for normal development of zebrafish embryosJinsong Zhang
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
Matrix Biol 22:279-93. 2003..Axis markers indicated that these effects likely involved processes occurring later than 10 h of embryogenesis... - Selective hydrolysis of triple-helical substrates by matrix metalloproteinase-2 and -9Janelle L Lauer-Fields
Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431 0991, USA
J Biol Chem 278:18140-5. 2003..THPs were found to provide highly selective substrates for members of the MMP family and can be used to evaluate active MMP production in cellular systems... - Analysis of matrix metalloproteinase triple-helical peptidase activity with substrates incorporating fluorogenic L- or D-amino acidsJanelle L Lauer-Fields
Department of Chemistry and Biochemistry, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431-0991, USA
Anal Biochem 321:105-15. 2003.... - Matrix metalloproteinase 1 interacts with neuronal integrins and stimulates dephosphorylation of AktKatherine Conant
Departments of Neurology and Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
J Biol Chem 279:8056-62. 2004..Together, these results suggest that MMP-1 can stimulate dephosphorylation of Akt and neuronal death through a non-proteolytic mechanism that involves changes in integrin signaling... - The roles of substrate thermal stability and P2 and P1' subsite identity on matrix metalloproteinase triple-helical peptidase activity and collagen specificityDmitriy Minond
Department of Chemistry and Biochemistry, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431-0991, USA
J Biol Chem 281:38302-13. 2006..Further exploration of MMP active sites and exosites, in combination with substrate conformation, may prove valuable for additional dissection of collagenolysis and yield information useful in the design of more selective MMP inhibitors... - Substrate conformation modulates aggrecanase (ADAMTS-4) affinity and sequence specificity. Suggestion of a common topological specificity for functionally diverse proteasesJanelle L Lauer-Fields
Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431 0991, USA
J Biol Chem 282:142-50. 2007..The triple-helical and single-stranded poly(Pro) II helical peptides represent the first synthetic substrates successfully designed for aggrecanases... - X-ray structure of human proMMP-1: new insights into procollagenase activation and collagen bindingDaniela Jozic
Max Planck Institut fur Biochemie, Abteilung Strukturforschung, Am Klopferspitz 18a, D 82152 Martinsried, Germany
J Biol Chem 280:9578-85. 2005..This is the first evidence of mobility of the Hpx domain in relation to the catalytic domain, providing an important clue toward the understanding of the collagenase-collagen interaction and subsequent collagenolysis... - Development of a solid-phase assay for analysis of matrix metalloproteinase activityJanelle L Lauer-Fields
Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL 33431-0991, USA
J Biomol Tech 15:305-16. 2004..The solid-phase assay is suitably flexible to allow studies of virtually any proteolytic enzyme for which appropriate substrates and antibodies are available... - Screening of potential a disintegrin and metalloproteinase with thrombospondin motifs-4 inhibitors using a collagen model fluorescence resonance energy transfer substrateJanelle L Lauer-Fields
Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL 33431, USA
Anal Biochem 373:43-51. 2008..Selective inhibitors for ADAMTS-4 would allow a more definitive evaluation of this protease in osteoarthritis and also represent a potential next generation in metalloproteinase therapeutics... - Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by induction of hepatocyte growth factor signalingCharlotte Kopitz
Institut für Experimentelle Onkologie und Therapieforschung, Universitat Munchen, Munich, Germany
Cancer Res 67:8615-23. 2007..Similar TIMP-1-associated changes in gene expression were detected in livers of patients with metastatic colorectal cancer. The newly identified role of TIMP-1 to create a prometastatic niche may also explain the TIMP-1 paradoxon... - Analysis of TIMP expression and activityLinda Troeberg
Methods Mol Med 135:251-67. 2007....
Research Grants
- METALLOPROTEASES IN CONNECTIVE TISSUE MATRIX BREAKDOWNHideaki Nagase; Fiscal Year: 1992....
- METALLOPROTEASES IN CONNECTIVE TISSUE MATRIX BREAKDOWNHideaki Nagase; Fiscal Year: 1993....
- METALLOPROTEASES IN CONNECTIVE TISSUE MATRIX BREAKDOWNHideaki Nagase; Fiscal Year: 2002..The principal investigator also proposes to examine the role of cell surface TIMP-2 in this activation process. ..