Original Article

Journal of Molecular Neuroscience

, Volume 26, Issue 1, pp 57-70

First online:

Neuregulins rescue PC12-ErbB-4 cells from cell death induced by β-amyloid peptide

Involvement of PI3K and PKC
  • Ayelet Di SegniAffiliated withDepartment of Neurobiochemistry, Tel-Aviv University
  • , Ezra ShaharabaniAffiliated withDepartment of Transplantation, Rabin Medical Center
  • , Reuven SteinAffiliated withDepartment of Neurobiochemistry, Tel-Aviv University
  • , Ronit Pinkas-KramarskiAffiliated withDepartment of Neurobiochemistry, Tel-Aviv University Email author 

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Neuregulins (NRGs), which are highly expressed in the nervous system, bind and activate two receptor tyrosine kinases, ErbB-3 and ErbB-4. We previously showed that NRG mediates survival of PC12-ErbB-4 cells from apoptosis induced by serum deprivation, tumor necrosis factor-α treatment, or H2O2. These effects of NRGs are mediated by the phosphoinositide 3-kinase (PI3K) signaling pathway. In the present study, we show that NRG induces a significant protective effect from β-amyloid 25–35 (Aβ[25–35]) peptide-induced cell death. The PI3K signaling pathway might be involved in this effect of NRG as the downstream effector of PI3K, protein kinase B (PKB/AkT), is activated by NRG in the presence of Aβ, and PKB/AkT activation is inhibited by the PI3K inhibitor, LY294002. In addition, our results demonstrate that Aβ-induced cell death is reduced by expression of activated PI3K. These results suggest that PI3K-dependent pathways might regulate the toxic effect of Aβ. In addition, Aβ induced alteration in the levels of the proapoptotic protein Bax. Neuregulin (NRG) treatment however, induced elevation in the levels of the antiapoptotic protein BclxL. The NRG-mediated BclxL elevation is regulated by protein kinase C (PKC), as NRG failed to elevate BclxL in the presence of the PKC inhibitor, GF109203X. Moreover, activation of PKC by phorbol 12-myristate 13-acetate markedly attenuated cell death induced by Aβ and induced elevation in BclxL levels. The results suggest that NRG might affect cell viability using two signaling pathways: activation of PI3K/PKB/AkT pathway and activation of PKC, which results in increasing levels of the antiapoptotic protein BclxL.

Index Entries

ErbB/HER family Neu differentiation factor neuregulin (NRG) signal transduction tyrosine kinase