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Hsp90–Akt phosphorylates ASK1 and inhibits ASK1-mediated apoptosis

Oncogene volume 24, pages 3954–3963 (2005)Cite this article

Abstract

Hsp90 client protein Akt has been shown to inhibit cell apoptosis in part by inhibiting proapoptotic kinase ASK1 (apoptosis signal-regulating kinase 1) activity. In the present study, we show that Hsp90 inhibits hydrogen peroxide (H2O2)-induced ASK1–p38 activation in endothelial cells (EC). The inhibitory effect of Hsp90 on ASK1–p38 activities is diminished when the Akt phosphorylation site on ASK1 (pSer83) is absent or when Akt is genetically deleted in cells, suggesting that Hsp90 and Akt function together to inhibit ASK1–p38 signaling. Thus, inhibition of Hsp90 by 17-allyamino-17-demethoxygeldanamycin (17-AAG) or phosphatidylinositol 3-kinase (PI3K) LY294002 induced and synergized ASK1 activation and ASK1-mediated EC apoptosis. Furthermore, we show that in resting EC Hsp90, Akt and ASK1 form a ternary complex in which both Akt and ASK1 bind to the middle domain of Hsp90, suggesting that Hsp90 may hold Akt and ASK1 in close proximity. The N-terminal domain of ASK1 containing the Akt phosphorylation site (pSer83) associates with Akt in resting state. However, Akt is released from the N-terminal domain concomitant with binding to the C-terminal domain of ASK1 in response to ASK1 activator H2O2, inhibitor of Hsp90 17-AAG and Akt inhibitor LY294002, leading to a more stable Hsp90-Akt–ASK1 complex. We conclude that Hsp90–Akt forms a complex with ASK1 and protect EC from stress-induced apoptosis.

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Acknowledgements

This work was supported by a grant from NIH Grants HL-65978 and AHA-0151259T to WM and HL-64793, HL-61371, HL-57665 and PO1 HL-70295 to WCS. Wang Min is an established investigator of the American Heart Association.

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Authors and Affiliations

  1. Interdepartmental Program in Vascular Biology and Transplantation and Department of Pathology, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT, 06510, USA

    Rong Zhang, Dianhong Luo, Lanfang Bai & Wang Min

  2. Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT, 06510, USA

    Robert Miao & William C Sessa

  3. Cell Signaling Technology, Inc., Beverly, MA, 01915, USA

    Qingyuan Ge

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  1. Rong Zhang
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Correspondence to Wang Min.

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Zhang, R., Luo, D., Miao, R. et al. Hsp90–Akt phosphorylates ASK1 and inhibits ASK1-mediated apoptosis. Oncogene 24, 3954–3963 (2005). https://doi.org/10.1038/sj.onc.1208548

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