Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) Exhibits an Important Intracellular Cleavage Function and Causes Chromosome Instability

Dmitri V Rozanov,Alex Y Strongin,Alexei Y Savinov,Sarah Boyd,Vladislav S Golubkov,Alexei V Chekanov,Albert Remacle,Andrei L Osterman,Stephen J Doxsey

doi:10.1074/jbc.m502779200

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.

Highlights

Elevated expression of membrane type-1 matrix metalloproteinase (MT1-MMP) is closely associated with malignancies
The centrosomal association of MT1-MMP was confirmed by using ␥- and ␣-tubulin as centrosomal and mitotic spindle markers, respectively
Only a fraction of MT1-MMP accumulates in centrosomes, whereas the bulk of cellular MT1-MMP is associated with the plasma membrane and the multiple intracellular vesicles (Fig. 1b)

Summary

Introduction

Elevated expression of membrane type-1 matrix metalloproteinase (MT1-MMP) is closely associated with malignancies. Active, functionally potent MT1-MMP degrades an integral centrosomal protein, pericentrin. Centrosomal MT1-MMP—We examined the subcellular localization of endogenously expressed MT1-MMP in breast carcinoma MCF7 and glioma U251 cells, both of which synthesize MT1-MMP naturally.

Results

Conclusion