title: MT-LOOP-dependent localization of membrane type I matrix metalloproteinase (MT1-MMP) to the cell adhesion complexes promotes cancer cell invasion.
abstract: Localization of membrane type I matrix metalloproteinase (MT1-MMP) to the leading edge is thought to be a crucial step during cancer cell invasion. However, its mechanisms and functional impact on cellular invasion have not been clearly defined. In this report, we have identified the MT-LOOP, a loop region in the catalytic domain of MT1-MMP ((163)PYAYIREG(170)), as an essential region for MT1-MMP to promote cellular invasion. Deletion of the MT-LOOP effectively inhibited functions of MT1-MMP on the cell surface, including proMMP-2 activation, degradation of gelatin and collagen films, and cellular invasion into a collagen matrix. This is not due to loss of the catalytic function of MT1-MMP but due to inefficient localization of the enzyme to β1-integrin-rich cell adhesion complexes at the plasma membrane. We also found that an antibody that specifically recognizes the MT-LOOP region of MT1-MMP (LOOPAb) inhibited MT1-MMP functions, fully mimicking the phenotype of the MT-LOOP deletion mutant. We therefore propose that the MT-LOOP region is an interface for molecular interactions that mediate enzyme localization to cell adhesion complexes and regulate MT1-MMP functions. Our findings have revealed a novel mechanism regulating MT1-MMP during cellular invasion and have identified the MT-LOOP as a potential exosite target region to develop selective MT1-MMP inhibitors.
authors.affiliation: From the Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Woskowicz
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Weaver
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Shitomi
authors.forename: Noriko
authors.initials: N
authors.lastname: Ito
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Itoh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002448:Cell Adhesion / Q000502:physiology*; D002522:Chlorocebus aethiops; D004792:Enzyme Precursors / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology; D018093:Gelatinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D004792:Enzyme Precursors; D011994:Recombinant Proteins; D018093:Gelatinases; C069860:progelatinase; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: Cell Invasion; Cell Surface Enzymes; Focal Adhesion; Integrin; Invasion; MT-LOOP; MT1-MMP; Matrix Metalloproteinase (MMP)