Neuregulin signaling through a PI3K/Akt/Bad pathway in Schwann cell survival.
beta-Neuregulin (betaNRG) is a potent Schwann cell survival factor that binds to and activates a heterodimeric ErbB2/ErbB3 receptor complex. We found that NRG receptor signaling rapidly activated phosphoinositide 3-kinase (PI3K) in serum-starved Schwann cells, while PI3K inhibitors markedly exacerbated apoptosis and completely blocked NRG-mediated rescue. NRG also rapidly signaled the phosphorylation of mitogen-activated protein kinase (MAPK) and the serine/threonine kinase Akt. The activation of Akt and MAPK in parallel pathways downstream from PI3K resulted in the phosphorylation of Bad at different serine residues. PI3K inhibitors that blocked NRG-mediated rescue also blocked the phosphorylation of Akt, MAPK, and Bad. However, selective inhibition of MEK-dependent Bad phosphorylation downstream from PI3K had no effect on NRG-mediated survival. Conversely, ectopic expression of wild-type Akt not only enhanced Bad phosphorylation but also enhanced autocrine- and NRG-mediated Schwann cell survival. Taken together, these results demonstrate that NRG receptor signaling through a PI3K/Akt/Bad pathway functions in Schwann cell survival.
Li
Y
Y
Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, 19104
Tennekoon
G I
GI
Birnbaum
M
M
Marchionni
M A
MA
Rutkowski
J L
JL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D020890:Neuregulin-1 / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D012583:Schwann Cells / Q000166:cytology* / Q000201:enzymology; D012584:Sciatic Nerve / Q000166:cytology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D051025:bcl-Associated Death Protein
D002352:Carrier Proteins; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051025:bcl-Associated Death Protein; C494821:Bad protein, rat; C117467:neuregulin beta; C494920:Akt1 protein, rat