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Published 5 July 2005. doi:10.1083/jcb.200502070
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 1, 61-72
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Article

Dissociation of Akt1 from its negative regulator JIP1 is mediated through the ASK1–MEK–JNK signal transduction pathway during metabolic oxidative stress

: a negative feedback loop



Jae J. Song and Yong J. Lee

Department of Surgery and Pharmacology, University of Pittsburgh, Pittsburgh, PA 15213

Correspondence to Yong J. Lee: leeyj{at}msx.upmc.edu

We have previously observed that metabolic oxidative stress–induced death domain–associated protein (Daxx) trafficking is mediated by the ASK1–SEK1–JNK1–HIPK1 signal transduction pathway. The relocalized Daxx from the nucleus to the cytoplasm during glucose deprivation participates in a positive regulatory feedback loop by binding to apoptosis signal–regulating kinase (ASK) 1. In this study, we report that Akt1 is involved in a negative regulatory feedback loop during glucose deprivation. Akt1 interacts with c-Jun NH2-terminal kinase (JNK)–interacting protein (JIP) 1, and Akt1 catalytic activity is inhibited. The JNK2-mediated phosphorylation of JIP1 results in the dissociation of Akt1 from JIP1 and subsequently restores Akt1 enzyme activity. Concomitantly, Akt1 interacts with stress-activated protein kinase/extracellular signal–regulated kinase (SEK) 1 (also known as MKK4) and inhibits SEK1 activity. Knockdown of SEK1 leads to the inhibition of JNK activation, JIP1–JNK2 binding, and the dissociation of Akt1 from JIP1 during glucose deprivation. Knockdown of JIP1 also leads to the inhibition of JNK activation, whereas the knockdown of Akt1 promotes JNK activation during glucose deprivation. Altogether, our data demonstrate that Akt1 participates in a negative regulatory feedback loop by interacting with the JIP1 scaffold protein.

Abbreviations used in this paper: ASK1, apoptosis signal–regulating kinase 1; Daxx, death domain–associated protein; DLK, dual zipper-bearing kinase; JIP1, JNK-interacting protein 1; JNK, c-Jun NH2-terminal kinase; MLK, mixed lineage protein kinase; MOI, multiplicity of infection; SEK1, stress-activated protein kinase/extracellular signal–regulated kinase1; si, small interference.


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