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J. Biol. Chem., Vol. 280, Issue 26, 25079-25086, July 1, 2005

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

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

From the Cancer Research Center, The Burnham Institute, La Jolla, California 92037, the School of Computer Science and Software Engineering, Monash University, Melbourne, Victoria 3800, Australia, and the ^¶University of Massachusetts Medical School, Worcester, Massachusetts 01605

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.

Received for publication, March 14, 2005 , and in revised form, May 3, 2005.

^* This work was supported by Grants CA77470 and CA83017 and by the Center on Proteolytic pathways Grant RR020843 (to A. Y. S.) from National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-713-6271; Fax: 858-646-3192; E-mail: strongin{at}burnham.org.

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