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J. Biol. Chem., Vol. 279, Issue 9, 8056-8062, February 27, 2004

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Matrix Metalloproteinase 1 Interacts with Neuronal Integrins and Stimulates Dephosphorylation of Akt^*

Katherine Conant, Coryse St. Hillaire, Hideaki Nagase¶||, Rob Visse¶||, Devin Gary||, Norman Haughey, Carol Anderson, Jadwiga Turchan, and Avindra Nath

From the Departments of Neurology and ^||Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287 and ^¶Department of Matrix Biology, The Kennedy Institute of Rheumatology, Imperial College, London W68LH, United Kingdom

Several studies have demonstrated that matrix metalloproteinases (MMPs) are cytotoxic. The responsible mechanisms, however, are not well understood. MMPs may promote cytotoxicity through their ability to disrupt or degrade matrix proteins that support cell survival, and MMPs may also cleave substrates to generate molecules that stimulate cell death. In addition, MMPs may themselves act on cell surface receptors that affect cell survival. Among such receptors is the ₂₁ integrin, a complex that has previously been linked to leukocyte death. In the present study we show that human neurons express ₂₁ and that pro-MMP-1 interacts with this integrin complex. We also show that stimulation of neuronal cultures with MMP-1 is associated with a rapid reduction in the phosphorylation of Akt, a kinase that can influence caspase activity and cell survival. Moreover, MMP-1-associated dephosphorylation of Akt is inhibited by a blocking antibody to the ₂ integrin, but not by batimastat, an inhibitor of MMP-1 enzymatic activity. Such dephosphorylation is also stimulated by a catalytic mutant of pro-MMP-1. Additional studies show that MMP-1 causes neuronal death, which is significantly diminished by both a general caspase inhibitor and anti-₂ but not by batimastat. Together, these results suggest that MMP-1 can stimulate dephosphorylation of Akt and neuronal death through a non-proteolytic mechanism that involves changes in integrin signaling.

Received for publication, July 2, 2003 , and in revised form, November 13, 2003.

^* This work was supported by National Institutes of Health Grant MH63722. 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: Johns Hopkins University, Dept. of Neurology, Pathology Bldg. Rm. 625, 600 North Wolfe St., Baltimore, MD 21287. Tel.: 410-502-7589; Fax: 410-502-7609; E-mail: kconant{at}mail.jhmi.edu.

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