Conformations of tissue plasminogen activator (tPA) orchestrate neuronal survival by a crosstalk between EGFR and NMDAR

被引:32
作者
Bertrand, T. [1 ]
Lesept, F. [1 ]
Chevilley, A. [1 ]
Lenoir, S. [1 ]
Aimable, M. [1 ]
Briens, A. [1 ]
Hommet, Y. [1 ]
Bardou, I. [1 ]
Parcq, J. [1 ]
Vivien, D. [1 ]
机构
[1] Univ Caen Basse Normandie, Serine Proteases & Pathophysiol Neurovasc Unit, INSERM, GIP Cyceron,U919, Caen, France
来源
CELL DEATH & DISEASE | 2015年 / 6卷
关键词
PROTEOLYTIC ACTIVITY; ISCHEMIC BRAIN; INVOLVEMENT; PATHWAY; BINDING; NEUROPROTECTION; EXCITOTOXICITY; PURIFICATION; CORECEPTOR; INCREASES;
D O I
10.1038/cddis.2015.296
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:e1924 / e1924
页数:9
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