Cell surface translocation of annexin A2 facilitates Glutamate-induced extracellular proteolysis

Mallika Valapala, Sayantan Maji, Julian Borejdo, Jamboor K. Vishwanatha

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Glutamate-induced elevation in intracellular Ca2+ 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 Ca2+- 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 Ca2+ imaging and time-lapse confocal microscopy demonstrated glutamate-induced Ca2+ 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 surfacetranslocated 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.

Original languageEnglish
Pages (from-to)15915-15926
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number23
DOIs
StatePublished - 6 Jun 2014

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