title: Neuregulins rescue PC12-ErbB-4 cells from cell death induced by beta-amyloid peptide: involvement of PI3K and PKC.
abstract: 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-alpha 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 beta-amyloid 25-35 (Abeta[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 Abeta, and PKB/AkT activation is inhibited by the PI3K inhibitor, LY294002. In addition, our results demonstrate that Abeta-induced cell death is reduced by expression of activated PI3K. These results suggest that PI3K-dependent pathways might regulate the toxic effect of Abeta. In addition, Abeta 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 Abeta 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.
authors.affiliation: Department of Neurobiochemistry, Tel-Aviv University, Ramat-Aviv, 69978, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Di Segni
authors.forename: Ezra
authors.initials: E
authors.lastname: Shaharabani
authors.forename: Reuven
authors.initials: R
authors.lastname: Stein
authors.forename: Ronit
authors.initials: R
authors.lastname: Pinkas-Kramarski
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D020890:Neuregulin-1 / Q000494:pharmacology*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D020890:Neuregulin-1; D011994:Recombinant Proteins; C117467:neuregulin beta; D019869:Phosphatidylinositol 3-Kinases; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate