title: Cell surface translocation of annexin A2 facilitates glutamate-induced extracellular proteolysis.
abstract: Glutamate-induced elevation in intracellular Ca(2+) has been implicated in excitotoxic cell death. Neurons respond to increased glutamate levels by activating an extracellular proteolytic cascade involving the components of the plasmin-plasminogen system. AnxA2 is a Ca(2+)-dependent phospholipid binding protein and serves as an extracellular proteolytic center by recruiting the tissue plasminogen activator and plasminogen and mediating the localized generation of plasmin. Ratiometric Ca(2+) imaging and time-lapse confocal microscopy demonstrated glutamate-induced Ca(2+) influx. We showed that glutamate translocated both endogenous and AnxA2-GFP to the cell surface in a process dependent on the activity of the NMDA receptor. Glutamate-induced translocation of AnxA2 is dependent on the phosphorylation of tyrosine 23 at the N terminus, and mutation of tyrosine 23 to a non-phosphomimetic variant inhibits the translocation process. The cell surface-translocated AnxA2 forms an active plasmin-generating complex, and this activity can be neutralized by a hexapeptide directed against the N terminus. These results suggest an involvement of AnxA2 in potentiating glutamate-induced cell death processes.
authors.affiliation: From the Department of Molecular and Medical Genetics and.
authors.forename: Mallika
authors.initials: M
authors.lastname: Valapala
authors.affiliation: From the Department of Molecular and Medical Genetics and.
authors.forename: Sayantan
authors.initials: S
authors.lastname: Maji
authors.affiliation: Department of Cell Biology and Immunology University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors.forename: Julian
authors.initials: J
authors.lastname: Borejdo
authors.affiliation: From the Department of Molecular and Medical Genetics and jamboor.vishwanatha@unthsc.edu.
authors.forename: Jamboor K
authors.initials: JK
authors.lastname: Vishwanatha
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002461:Cell Line, Transformed; D005110:Extracellular Space; D005341:Fibrinolysin / Q000378:metabolism; D018698:Glutamic Acid / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D051379:Mice; D010766:Phosphorylation; D021381:Protein Transport; D059748:Proteolysis; D014443:Tyrosine / Q000378:metabolism
chemical_list: D017306:Annexin A2; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D014443:Tyrosine; D005341:Fibrinolysin; D002118:Calcium
keywords: Annexin; Calcium; Cell Surface Protein; Glutamate; Plasmin; Proteolysis
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