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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.

Song JJ, Lee YJ - J. Cell Biol. (2005)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery and Pharmacology, University of Pittsburgh, Pittsburgh, PA 15213, USA.

ABSTRACT
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 NH(2)-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.

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Glucose deprivation–induced JNK activation in control plasmid (pSilencer), pSilencer-siJIP1 stably transfected siJIP1#2, or Ad.Flag-JIP1–infected siJIP1#2 cells. Cells were exposed to glucose-free medium for various times (10–120 min; A) or for 60 min (B). Cell lysates were immunoblotted with anti–ACTIVE JNK, anti-JNK2, anti-JIP1, or antiactin antibody.
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fig9: Glucose deprivation–induced JNK activation in control plasmid (pSilencer), pSilencer-siJIP1 stably transfected siJIP1#2, or Ad.Flag-JIP1–infected siJIP1#2 cells. Cells were exposed to glucose-free medium for various times (10–120 min; A) or for 60 min (B). Cell lysates were immunoblotted with anti–ACTIVE JNK, anti-JNK2, anti-JIP1, or antiactin antibody.

Mentions: To examine whether JIP1 plays an important role in JNK activation during glucose deprivation, pSilencer control plasmid–transfected cells or pSilencer-siJIP1 stably transfected siJIP1#2 cells were exposed to glucose-free medium for various times (Fig. 9 A) or for 60 min (Fig. 9 B). Fig. 9 shows that glucose deprivation–induced JNK activation was suppressed in siJIP1#2 cells. Because JIP1 was a knockdown, but not a knockout, in siJIP1#2 cells, basal levels of activated JNK was still observed. The activation of JNK was restored by overexpressing JIP1 in siJIP1#2 cells (Fig. 9 A, right).


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.

Song JJ, Lee YJ - J. Cell Biol. (2005)

Glucose deprivation–induced JNK activation in control plasmid (pSilencer), pSilencer-siJIP1 stably transfected siJIP1#2, or Ad.Flag-JIP1–infected siJIP1#2 cells. Cells were exposed to glucose-free medium for various times (10–120 min; A) or for 60 min (B). Cell lysates were immunoblotted with anti–ACTIVE JNK, anti-JNK2, anti-JIP1, or antiactin antibody.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171369&req=5

fig9: Glucose deprivation–induced JNK activation in control plasmid (pSilencer), pSilencer-siJIP1 stably transfected siJIP1#2, or Ad.Flag-JIP1–infected siJIP1#2 cells. Cells were exposed to glucose-free medium for various times (10–120 min; A) or for 60 min (B). Cell lysates were immunoblotted with anti–ACTIVE JNK, anti-JNK2, anti-JIP1, or antiactin antibody.
Mentions: To examine whether JIP1 plays an important role in JNK activation during glucose deprivation, pSilencer control plasmid–transfected cells or pSilencer-siJIP1 stably transfected siJIP1#2 cells were exposed to glucose-free medium for various times (Fig. 9 A) or for 60 min (Fig. 9 B). Fig. 9 shows that glucose deprivation–induced JNK activation was suppressed in siJIP1#2 cells. Because JIP1 was a knockdown, but not a knockout, in siJIP1#2 cells, basal levels of activated JNK was still observed. The activation of JNK was restored by overexpressing JIP1 in siJIP1#2 cells (Fig. 9 A, right).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery and Pharmacology, University of Pittsburgh, Pittsburgh, PA 15213, USA.

ABSTRACT
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 NH(2)-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.

Show MeSH
Related in: MedlinePlus