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, Avindra Nath

Research output: Contribution to journalArticle

Abstract

Several studies have demonstrated that matrix metal-loproteinases (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 α21 integrin, a complex that has previously been linked to leukocyte death. In the present study we show that human neurons express α21 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 α2 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-α2 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.

Original languageEnglish (US)
Pages (from-to)8056-8062
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number9
DOIs
StatePublished - Feb 27 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Conant, K., St. Hillaire, C., Nagase, H., Visse, R., Gary, D., Haughey, N., Anderson, C., Turchan, J., & Nath, A. (2004). Matrix Metalloproteinase 1 Interacts with Neuronal Integrins and Stimulates Dephosphorylation of Akt. Journal of Biological Chemistry, 279(9), 8056-8062. https://doi.org/10.1074/jbc.M307051200