JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3.
Life and death decisions are made by integrating a variety of apoptotic and survival signals in mammalian cells. Therefore, there is likely to be a common mechanism that integrates multiple signals adjudicating between the alternatives. In this study, we propose that 14-3-3 represents such an integration point. Several proapoptotic proteins commonly become associated with 14-3-3 upon phosphorylation by survival-mediating kinases such as Akt. We reported previously that cellular stresses induce c-Jun NH2-terminal kinase (JNK)-mediated 14-3-3zeta phosphorylation at Ser184 (Tsuruta, F., J. Sunayama, Y. Mori, S. Hattori, S. Shimizu, Y. Tsujimoto, K. Yoshioka, N. Masuyama, and Y. Gotoh. 2004. EMBO J. 23:1889-1899). Here, we show that phosphorylation of 14-3-3 by JNK releases the proapoptotic proteins Bad and FOXO3a from 14-3-3 and antagonizes the effects of Akt signaling. As a result of dissociation, Bad is dephosphorylated and translocates to the mitochondria, where it associates with Bcl-2/Bcl-x(L). Because Bad and FOXO3a share the 14-3-3-binding motif with other proapoptotic proteins, we propose that this JNK-mediated phosphorylation of 14-3-3 regulates these proapoptotic proteins in concert and makes cells more susceptible to apoptotic signals.
Sunayama
Jun
J
Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
Tsuruta
Fuminori
F
Masuyama
Norihisa
N
Gotoh
Yukiko
Y
D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002522:Chlorocebus aethiops; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
D048948:14-3-3 Proteins; C494819:BAD protein, human; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases