title: Akt negatively regulates the cJun N-terminal kinase pathway in PC12 cells.
abstract: The protein serine/threonine kinase Akt is a target of phosphatidylinositol 3-kinase that mediates many of the trophic actions of growth factors on cells. In PC12 cells, complete removal of serum leads to rapid stimulation of the cJun N-terminal kinase (JNK) pathway. Inclusion of insulin-like growth factor-1, a stimulator of Akt in PC12 cells, inhibits JNK activation in this setting, whereas addition of wortmannin to PC12 cells in the presence of serum stimulates JNK activity, suggesting that growth factor-mediated signaling through the phosphatidylinositol 3-kinase/Akt pathway chronically inhibits the JNK pathway in PC12 cells. To explore the possible role of Akt as a negative regulator of JNK activity in PC12 cells, a myristoylated, gain-of-function Akt polypeptide (Myr-Akt) was expressed by retrovirus-mediated gene transfer. Stimulation of JNK activity by serum withdrawal or UV irradiation in PC12 cell clones stably expressing Myr-Akt was inhibited approximately 95% or 50%, respectively, relative to control transfected PC12 cells. Phosphorylation of both JNKs and a proximal activator, MAP kinase kinase 4 (MKK4), in response to UV irradiation was inhibited in Myr-Akt-expressing PC12 cells. Furthermore, transient expression of Myr-Akt strongly inhibited cJun transactivation mediated by MEKK1 or MKK7-JNK3, a gain-of-function MKK7-JNK fusion protein. Interestingly, inhibited JNK activation in the Myr-Akt-expressing PC12 cells is associated with marked induction of JNK-interacting protein-1 (JIP-1). We propose that negative regulation of the JNK pathway through Akt-dependent induction of specfic JIP proteins contributes to the antiapoptotic actions of Akt in neuronal cell types.
authors: Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors: V
authors: V
authors: Levresse
authors: L
authors: L
authors: Butterfield
authors: E
authors: E
authors: Zentrich
authors: L E
authors: LE
authors: Heasley
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D019439:Chromaffin Cells / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection / Q000379:methods
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C110528:Mapk8ip1 protein, rat; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D007334:Insulin-Like Growth Factor I; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases