Membrane type-1 matrix metalloproteinase (MT1-MMP) exhibits an important intracellular cleavage function and causes chromosome instability.
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.
Golubkov
Vladislav S
VS
Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA.
Boyd
Sarah
S
Savinov
Alexei Y
AY
Chekanov
Alexei V
AV
Osterman
Andrei L
AL
Remacle
Albert
A
Rozanov
Dmitri V
DV
Doxsey
Stephen J
SJ
Strongin
Alex Y
AY
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
D000941:Antigens; D002843:Chromatin; D010455:Peptides; D020543:Proteome; D034741:RNA, Small Interfering; D014404:Tubulin; C086178:pericentrin; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases