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Akt Regulates TNFα synthesis downstream of RIP1 kinase activation during necroptosis.

McNamara CR, Ahuja R, Osafo-Addo AD, Barrows D, Kettenbach A, Skidan I, Teng X, Cuny GD, Gerber S, Degterev A - PLoS ONE (2013)

Bottom Line: In L929 cells, this activation requires independent signaling inputs from both growth factors and RIP1.Akt controls necroptosis through downstream targeting of mammalian Target of Rapamycin complex 1 (mTORC1).Overall, our results provide new insights into the mechanism of necroptosis and the role of Akt kinase in both cell death and inflammatory regulation.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Biochemistry, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachussets, United States of America.

ABSTRACT
Necroptosis is a regulated form of necrotic cell death that has been implicated in the pathogenesis of various diseases including intestinal inflammation and systemic inflammatory response syndrome (SIRS). In this work, we investigated the signaling mechanisms controlled by the necroptosis mediator receptor interacting protein-1 (RIP1) kinase. We show that Akt kinase activity is critical for necroptosis in L929 cells and plays a key role in TNFα production. During necroptosis, Akt is activated in a RIP1 dependent fashion through its phosphorylation on Thr308. In L929 cells, this activation requires independent signaling inputs from both growth factors and RIP1. Akt controls necroptosis through downstream targeting of mammalian Target of Rapamycin complex 1 (mTORC1). Akt activity, mediated in part through mTORC1, links RIP1 to JNK activation and autocrine production of TNFα. In other cell types, such as mouse lung fibroblasts and macrophages, Akt exhibited control over necroptosis-associated TNFα production without contributing to cell death. Overall, our results provide new insights into the mechanism of necroptosis and the role of Akt kinase in both cell death and inflammatory regulation.

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Model of RIP1, Akt and JNK dependent signaling in necroptotic L929 cells.Akt phosphorylation at Thr308 during necroptosis requires inputs from both growth factors and RIP1 kinase. Downstream from Akt, JNK activation leads to TNFα synthesis. Activation of Akt during necroptosis also leads the phosphorylation of several known Akt substrates, such as mTOR, which contribute to the execution of necroptotic death in L929 cells.
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pone-0056576-g009: Model of RIP1, Akt and JNK dependent signaling in necroptotic L929 cells.Akt phosphorylation at Thr308 during necroptosis requires inputs from both growth factors and RIP1 kinase. Downstream from Akt, JNK activation leads to TNFα synthesis. Activation of Akt during necroptosis also leads the phosphorylation of several known Akt substrates, such as mTOR, which contribute to the execution of necroptotic death in L929 cells.

Mentions: In this study we investigated RIP1 kinase-dependent signaling pathways using mouse fibrosarcoma L929 cells that die by necroptosis when treated with the pan-caspase inhibitor zVAD.fmk. Altogether, our results suggest that Akt kinase is specifically engaged in signaling downstream from RIP1 kinase, which leads to a selective increase in its phosphorylation on Thr308, but not Ser473. According to our model (Fig. 9), necroptosis-associated phosphorylation of Akt requires two distinct signals. The first input, which is induced by growth factors, leads to the plasma membrane localization of Akt. Expression of a constitutively membrane-targeted Akt construct, Myr-Akt, overcomes the requirement for growth factors. At the same time, expression of Myr-Akt alone is not sufficient for the induction of necroptosis. A second, RIP1 kinase-dependent input is required for Thr308 phosphorylation of Akt in response to caspase inhibition and is essential for the propagation of the necroptotic signal.


Akt Regulates TNFα synthesis downstream of RIP1 kinase activation during necroptosis.

McNamara CR, Ahuja R, Osafo-Addo AD, Barrows D, Kettenbach A, Skidan I, Teng X, Cuny GD, Gerber S, Degterev A - PLoS ONE (2013)

Model of RIP1, Akt and JNK dependent signaling in necroptotic L929 cells.Akt phosphorylation at Thr308 during necroptosis requires inputs from both growth factors and RIP1 kinase. Downstream from Akt, JNK activation leads to TNFα synthesis. Activation of Akt during necroptosis also leads the phosphorylation of several known Akt substrates, such as mTOR, which contribute to the execution of necroptotic death in L929 cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585731&req=5

pone-0056576-g009: Model of RIP1, Akt and JNK dependent signaling in necroptotic L929 cells.Akt phosphorylation at Thr308 during necroptosis requires inputs from both growth factors and RIP1 kinase. Downstream from Akt, JNK activation leads to TNFα synthesis. Activation of Akt during necroptosis also leads the phosphorylation of several known Akt substrates, such as mTOR, which contribute to the execution of necroptotic death in L929 cells.
Mentions: In this study we investigated RIP1 kinase-dependent signaling pathways using mouse fibrosarcoma L929 cells that die by necroptosis when treated with the pan-caspase inhibitor zVAD.fmk. Altogether, our results suggest that Akt kinase is specifically engaged in signaling downstream from RIP1 kinase, which leads to a selective increase in its phosphorylation on Thr308, but not Ser473. According to our model (Fig. 9), necroptosis-associated phosphorylation of Akt requires two distinct signals. The first input, which is induced by growth factors, leads to the plasma membrane localization of Akt. Expression of a constitutively membrane-targeted Akt construct, Myr-Akt, overcomes the requirement for growth factors. At the same time, expression of Myr-Akt alone is not sufficient for the induction of necroptosis. A second, RIP1 kinase-dependent input is required for Thr308 phosphorylation of Akt in response to caspase inhibition and is essential for the propagation of the necroptotic signal.

Bottom Line: In L929 cells, this activation requires independent signaling inputs from both growth factors and RIP1.Akt controls necroptosis through downstream targeting of mammalian Target of Rapamycin complex 1 (mTORC1).Overall, our results provide new insights into the mechanism of necroptosis and the role of Akt kinase in both cell death and inflammatory regulation.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Biochemistry, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachussets, United States of America.

ABSTRACT
Necroptosis is a regulated form of necrotic cell death that has been implicated in the pathogenesis of various diseases including intestinal inflammation and systemic inflammatory response syndrome (SIRS). In this work, we investigated the signaling mechanisms controlled by the necroptosis mediator receptor interacting protein-1 (RIP1) kinase. We show that Akt kinase activity is critical for necroptosis in L929 cells and plays a key role in TNFα production. During necroptosis, Akt is activated in a RIP1 dependent fashion through its phosphorylation on Thr308. In L929 cells, this activation requires independent signaling inputs from both growth factors and RIP1. Akt controls necroptosis through downstream targeting of mammalian Target of Rapamycin complex 1 (mTORC1). Akt activity, mediated in part through mTORC1, links RIP1 to JNK activation and autocrine production of TNFα. In other cell types, such as mouse lung fibroblasts and macrophages, Akt exhibited control over necroptosis-associated TNFα production without contributing to cell death. Overall, our results provide new insights into the mechanism of necroptosis and the role of Akt kinase in both cell death and inflammatory regulation.

Show MeSH
Related in: MedlinePlus