Matrix metalloproteinase 1 interacts with neuronal integrins and stimulates dephosphorylation of Akt.
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 alpha(2)beta(1) integrin, a complex that has previously been linked to leukocyte death. In the present study we show that human neurons express alpha(2)beta(1) 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 alpha(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-alpha(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.
Conant
Katherine
K
Departments of Neurology and Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. kconant@mail.jhmi.edu
St Hillaire
Coryse
C
Nagase
Hideaki
H
Visse
Rob
R
Gary
Devin
D
Haughey
Norman
N
Anderson
Carol
C
Turchan
Jadwiga
J
Nath
Avindra
A
D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000166:cytology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D038982:Integrin alpha2beta1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009474:Neurons / Q000737:chemistry*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation; D011498:Protein Precursors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D015398:Signal Transduction; D013876:Thiophenes / Q000494:pharmacology
D000906:Antibodies; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D038982:Integrin alpha2beta1; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1