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Tissue‐type plasminogen activator rescues neurones from serum deprivation‐induced apoptosis through a mechanism independent of its proteolytic activity

2006; Wiley; Volume: 98; Issue: 5 Linguagem: Inglês

10.1111/j.1471-4159.2006.03982.x

1471-4159

Géraldine Liot, Benoit D. Roussel, Nathalie Lebeurrier, Karim Benchenane, José P. López‐Atalaya, Denis Vivien, Carine Ali,

Cell death mechanisms and regulation

Although the mechanism of action of tissue-type plasminogen activator (tPA) in excitotoxic necrosis is well documented, whether this serine protease can influence the apoptotic cascade remains a subject of debate. Here, we report that tPA protects cultured cortical neurones against apoptotic cell death induced by serum deprivation, an effect associated with a reduction of caspase-3 activation. Interestingly, blocking tPA proteolytic activity by either tPA stop or neuroserpin did not prevent this neuroprotection. Similarly, prevention of the interaction between tPA and its receptor low-density lipoprotein receptor-related protein (LRP) could not alter tPA anti-apoptotic activity. Interestingly, the survival-promoting effect of tPA was blocked by the phosphatidylinositol-3 (PI-3) kinase inhibitor, LY294002, but not by the mitogen-activated protein (MAP) kinase inhibitor, U0126. In conclusion, the present demonstration of an anti-apoptotic effect of tPA, independent of its enzymatic activity, reveals an additional level of complexity in our understanding of this critical mediator of brain physiology and pathology.