Abstract
N-cadherin is a major adhesion molecule involved in the development and plasticity of the nervous system. N-cadherin-mediated cell adhesion regulates neuroepithelial cell polarity, neuronal precursor migration, growth cone migration and synaptic plasticity. In vitro, it has been involved in signaling events regulating processes such as cell mobility, proliferation and differentiation. N-cadherin has also been implicated in adhesion-dependent protection against apoptosis in non-neuronal cells. In this study, we investigated if the engagement of N-cadherin participates to the control of neuronal cells survival/death balance. We observed that plating either primary mouse spinal cord neurons or primary rat hippocampal neurons on N-cadherin recombinant substrate greatly enhances their survival compared to non-specific adhesion on poly-L-lysine. We show that N-cadherin engagement, in the absence of other survival factors (cell-matrix interactions and serum), protects GT1-7 neuronal cells against apoptosis. Using this cell line, we then searched for the signaling pathways involved in the survival effect of N-cadherin engagement. The PI3-kinase/Akt survival pathway and its downstream effector Bad are not involved, as no phosphorylation of Akt or Bad proteins in response to N-cadherin engagement was observed. In contrast, N-cadherin engagement activated the Erk1/2 MAP kinase pathway. Moreover, N-cadherin ligation mediated a 2-fold decrease in the level of the pro-apoptotic protein Bim-EL whereas the level of the anti-apoptotic protein Bcl-2 was unchanged. Inhibition of Mek1/2 kinases with U0126, and the resulting inhibition of Erk1/2 phosphorylation, induced the increase of both the level of Bim-EL and apoptosis of cells seeded on the N-cadherin substrate, suggesting that Erk phosphorylation is necessary for cell survival. Finally, the overexpression of a phosphorylation defective form of Bim-EL prevented N-cadherin-engagement induced cell survival. In conclusion, our results show that N-cadherin engagement mediates neuronal cell survival by enhancing the MAP kinase pathway and down-regulating the pro-apoptotic protein Bim-EL.
Highlights
Cadherins are a family of transmembrane proteins that mediate calcium-dependent homophilic cell-cell contacts
The mechanisms whereby cadherin adhesion contributes to cell fate by regulating the survival/cell death balance is poorly understood by comparison to the well-known molecular mechanism of anoıkis (apoptosis induced by the loss of cell contacts with the extracellular matrix (ECM)) [10]
Our work demonstrates that Ncadherin-mediated adhesion provides neuronal cells with prosurvival signal, protecting them from apoptosis in the absence of growth factors and extracellular matrix stimuli
Summary
Cadherins are a family of transmembrane proteins that mediate calcium-dependent homophilic cell-cell contacts. They provide anchorage in between neighboring cells by interacting with the actin cytoskeleton through catenins [1]. Cadherin-mediated cell-cell interactions may regulate the balance between cell survival and cell death during development and maintenance of tissue homeostasis. The mechanisms whereby cadherin adhesion contributes to cell fate by regulating the survival/cell death balance is poorly understood by comparison to the well-known molecular mechanism of anoıkis (apoptosis induced by the loss of cell contacts with the extracellular matrix (ECM)) [10]. The initiation and execution of anoıkis, which is refrained in physiological conditions by integrin engagement, is mediated by different pathways that all converge to the regulation of anti-apoptotic and pro-apoptotic Bcl family proteins, leading to activation of caspases and subsequent activation of endonucleases, DNA fragmentation and eventually cell death [10]
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