title: Membrane type-1 matrix metalloproteinase (MT1-MMP) exhibits an important intracellular cleavage function and causes chromosome instability.
abstract: Elevated expression of membrane type-1 matrix metalloproteinase (MT1-MMP) is closely associated with malignancies. There is a consensus among scientists that cell surface-associated MT1-MMP is a key player in pericellular proteolytic events. Now we have identified an intracellular, hitherto unknown, function of MT1-MMP. We demonstrated that MT1-MMP is trafficked along the tubulin cytoskeleton. A fraction of cellular MT1-MMP accumulates in the centrosomal compartment. MT1-MMP targets an integral centrosomal protein, pericentrin. Pericentrin is known to be essential to the normal functioning of centrosomes and to mitotic spindle formation. Expression of MT1-MMP stimulates mitotic spindle aberrations and aneuploidy in non-malignant cells. Volumes of data indicate that chromosome instability is an early event of carcinogenesis. In agreement, the presence of MT1-MMP activity correlates with degraded pericentrin in tumor biopsies, whereas normal tissues exhibit intact pericentrin. We believe that our data show a novel proteolytic pathway to chromatin instability and elucidate the close association of MT1-MMP with malignant transformation.
authors.affiliation: Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA.
authors.forename: Vladislav S
authors.initials: VS
authors.lastname: Golubkov
authors.forename: Sarah
authors.initials: S
authors.lastname: Boyd
authors.forename: Alexei Y
authors.initials: AY
authors.lastname: Savinov
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Chekanov
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Osterman
authors.forename: Albert
authors.initials: A
authors.lastname: Remacle
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Rozanov
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Doxsey
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
mesh_terms: D000818:Animals; D000941:Antigens / Q000737:chemistry; D001665:Binding Sites; D045744:Cell Line, Tumor; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic; D018385:Centrosome / Q000378:metabolism / Q000648:ultrastructure; D002843:Chromatin / Q000737:chemistry; D002875:Chromosomes / Q000378:metabolism* / Q000648:ultrastructure; D003599:Cytoskeleton / Q000378:metabolism; D004285:Dogs; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D013058:Mass Spectrometry; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism / Q000502:physiology*; D008677:Metaphase; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009369:Neoplasms / Q000473:pathology; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D020543:Proteome; D034741:RNA, Small Interfering / Q000378:metabolism; D008941:Spindle Apparatus; D014404:Tubulin / Q000737:chemistry
chemical_list: D000941:Antigens; D002843:Chromatin; D010455:Peptides; D020543:Proteome; D034741:RNA, Small Interfering; D014404:Tubulin; C086178:pericentrin; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases