PMID- 26469972
OWN - NLM
STAT- MEDLINE
DCOM- 20160621
LR  - 20181202
IS  - 2041-4889 (Electronic)
VI  - 6
IP  - 10
DP  - 2015 Oct 15
TI  - Conformations of tissue plasminogen activator (tPA) orchestrate neuronal survival 
      by a crosstalk between EGFR and NMDAR.
PG  - e1924
LID - 10.1038/cddis.2015.296 [doi]
AB  - Tissue-type plasminogen activator (tPA) is a pleiotropic serine protease of the 
      central nervous system (CNS) with reported neurotrophic and neurotoxic functions. 
      Produced and released under its single chain form (sc), the sc-tPA can be cleaved 
      by plasmin or kallikrein in a two chain form, tc-tPA. Although both sc-tPA and 
      tc-tPA display a similar fibrinolytic activity, we postulated here that these two 
      conformations of tPA (sc-tPA and tc-tPA) could differentially control the effects 
      of tPA on neuronal survival. Using primary cultures of mouse cortical neurons, 
      our present study reveals that sc-tPA is the only one capable to promote 
      N-methyl-D-aspartate receptor (NMDAR)-induced calcium influx and subsequent 
      excitotoxicity. In contrast, both sc-tPA and tc-tPA are capable to activate 
      epidermal growth factor receptors (EGFRs), a mechanism mediating the 
      antiapoptotic effects of tPA. Interestingly, we revealed a tPA dependent 
      crosstalk between EGFR and NMDAR in which a tPA-dependent activation of EGFRs 
      leads to downregulation of NMDAR signaling and to subsequent neurotrophic 
      effects.
FAU - Bertrand, T
AU  - Bertrand T
AD  - Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular 
      Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
FAU - Lesept, F
AU  - Lesept F
AD  - Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular 
      Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
FAU - Chevilley, A
AU  - Chevilley A
AD  - Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular 
      Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
FAU - Lenoir, S
AU  - Lenoir S
AD  - Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular 
      Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
FAU - Aimable, M
AU  - Aimable M
AD  - Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular 
      Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
FAU - Briens, A
AU  - Briens A
AD  - Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular 
      Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
FAU - Hommet, Y
AU  - Hommet Y
AD  - Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular 
      Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
FAU - Bardou, I
AU  - Bardou I
AD  - Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular 
      Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
FAU - Parcq, J
AU  - Parcq J
AD  - Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular 
      Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
FAU - Vivien, D
AU  - Vivien D
AD  - Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular 
      Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151015
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 3.4.21.68 (PLAT protein, human)
RN  - EC 3.4.21.68 (Tissue Plasminogen Activator)
SB  - IM
MH  - Apoptosis
MH  - Calcium Signaling
MH  - Cell Survival
MH  - ErbB Receptors/*metabolism
MH  - Female
MH  - Humans
MH  - Protein Conformation
MH  - Receptor Cross-Talk
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Tissue Plasminogen Activator/chemistry/*physiology
PMC - PMC4632317
EDAT- 2015/10/16 06:00
MHDA- 2016/06/22 06:00
PMCR- 2015/10/01
CRDT- 2015/10/16 06:00
PHST- 2015/04/08 00:00 [received]
PHST- 2015/07/27 00:00 [revised]
PHST- 2015/08/17 00:00 [accepted]
PHST- 2015/10/16 06:00 [entrez]
PHST- 2015/10/16 06:00 [pubmed]
PHST- 2016/06/22 06:00 [medline]
PHST- 2015/10/01 00:00 [pmc-release]
AID - cddis2015296 [pii]
AID - 10.1038/cddis.2015.296 [doi]
PST - epublish
SO  - Cell Death Dis. 2015 Oct 15;6(10):e1924. doi: 10.1038/cddis.2015.296.