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Dual engagement of 14-3-3 proteins controls signal relay from ASK2 to the ASK1 signalosome

Oncogene volume 29, pages 822–830 (2010)Cite this article

Abstract

Faithful and efficient transmission of biological signals through mitogen-activated protein kinase (MAPK) pathways requires engagement of highly regulated cellular machinery in response to diverse environmental cues. Here, we report a novel mechanism controlling signal relay between two MAP3Ks, apoptosis signal-regulating kinase (ASK) 1 and ASK2. We show that ASK2 specifically interacts with 14-3-3 proteins through phosphorylated S964. Although a 14-3-3-binding defective mutant of ASK1 (S967A) has no effect on the ASK2/14-3-3 interaction, both overexpression of the analogous ASK2 (S964A) mutant and knockdown of ASK2 dramatically reduced the amount of ASK1 complexed with 14-3-3. These data suggest a dominant role of ASK2 in 14-3-3 control of ASK1 function. Indeed, ASK2 S964A-induced dissociation of 14-3-3 from ASK1 correlated with enhanced phosphorylation of ASK1 at T838 and increased c-Jun N-terminal kinase phosphorylation, the two biological readouts of ASK1 activation. Our results suggest a model in which upstream signals couple ASK2 S964 phosphorylation to the ASK1 signalosome through dual engagement of 14-3-3.

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Acknowledgements

We thank the past and present members of the Fu laboratory for many stimulating discussions, as well as Zhengbin Yao for helpful suggestions. This work was supported by a National Cancer Institute National Research Service Award Grant 5F31CA117057 and a National Science Foundation Facilitating Academic Careers in Engineering and Science Fellowship 0450303 (I6660663) to LMC, an NIH Pharmacological Sciences Training Grant T32 GM008602 to MCP, NIH Grant RO1GM53165 and Emory URC grant to HF, and NIH/NCI Grant PO1CA116676 and USAMRMC05075002 to FRK and HF. HF is a Georgia Research Alliance Distinguished Investigator, and FRK and HF are Georgia Cancer Coalition Distinguished Cancer Scholars.

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  1. L M Cockrell and M C Puckett: These authors contributed equally to this work.

Authors and Affiliations

  1. Program in Molecular and Systems Pharmacology of the Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA, USA

    L M Cockrell, M C Puckett, E H Goldman & H Fu

  2. Department of Pharmacology, Emory University, Rollins Research Center, Atlanta, GA, USA

    L M Cockrell, M C Puckett, E H Goldman & H Fu

  3. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA

    F R Khuri & H Fu

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  1. L M Cockrell
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  2. M C Puckett
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  3. E H Goldman
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  4. F R Khuri
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  5. H Fu
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Correspondence to H Fu.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Cockrell, L., Puckett, M., Goldman, E. et al. Dual engagement of 14-3-3 proteins controls signal relay from ASK2 to the ASK1 signalosome. Oncogene 29, 822–830 (2010). https://doi.org/10.1038/onc.2009.382

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