TY - JOUR
T1 - Neuregulin induces sustained reactive oxygen species generation to mediate neuronal differentiation
AU - Goldsmit, Yona
AU - Erlich, Shlomit
AU - Pinkas-Kramarski, Ronit
N1 - Funding Information:
This work was supported in part by The National Institute for Psychobiology in Israel, Charles E. Smith Fund, grant No. 7-2001 and by the Israel Science Foundation Grant 434/01-1. We thank Prof. Y. Kloog for critically reading this manuscript.
PY - 2001
Y1 - 2001
N2 - Neuregulins (NRGs), which are highly expressed in the nervous system, bind and activate two receptor tyrosine kinases, ErbB-3 and ErbB-4. Recently, we have shown that ErbB-4 receptors expressed in PC12 cells mediate NRG-induced differentiation through the MAPK signaling pathway. Here we demonstrate that NRG induces an increase in the intracellular concentration of reactive oxygen species (ROS). N-acetylcysteine, a ROS scavenger, inhibited NRG-induced activation of Ras and Erk and PC12-ErbB-4 cell differentiation. These results suggest that ROS production is involved in NRG-mediated neuronal differentiation and that ROS can regulate activation of Ras and Erk. Constitutively active Ras enhanced ROS production and dominant negative Ras inhibited NRG-induced ROS production, suggesting, a positive regulatory loop between Ras and ROS. The mitogen, EGF, induced short-term ROS production whereas NRG and NGF, which induce cell differentiation, induced prolonged ROS production. These results strongly suggest that the kinetics of ROS production may determine whether the cells will differentiate or proliferate.
AB - Neuregulins (NRGs), which are highly expressed in the nervous system, bind and activate two receptor tyrosine kinases, ErbB-3 and ErbB-4. Recently, we have shown that ErbB-4 receptors expressed in PC12 cells mediate NRG-induced differentiation through the MAPK signaling pathway. Here we demonstrate that NRG induces an increase in the intracellular concentration of reactive oxygen species (ROS). N-acetylcysteine, a ROS scavenger, inhibited NRG-induced activation of Ras and Erk and PC12-ErbB-4 cell differentiation. These results suggest that ROS production is involved in NRG-mediated neuronal differentiation and that ROS can regulate activation of Ras and Erk. Constitutively active Ras enhanced ROS production and dominant negative Ras inhibited NRG-induced ROS production, suggesting, a positive regulatory loop between Ras and ROS. The mitogen, EGF, induced short-term ROS production whereas NRG and NGF, which induce cell differentiation, induced prolonged ROS production. These results strongly suggest that the kinetics of ROS production may determine whether the cells will differentiate or proliferate.
KW - Epidermal growth factor (EGF)
KW - ErbB/HER family
KW - Neu differentiation factor (NDF)
KW - Neuregulin (NRG)
KW - Reactive oxygen species (ROS)
KW - Signal transduction
KW - Tyrosine kinase
UR - http://www.scopus.com/inward/record.url?scp=0035567134&partnerID=8YFLogxK
U2 - 10.1023/A:1015108306171
DO - 10.1023/A:1015108306171
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AN - SCOPUS:0035567134
SN - 0272-4340
VL - 21
SP - 753
EP - 769
JO - Cellular and Molecular Neurobiology
JF - Cellular and Molecular Neurobiology
IS - 6
ER -