Faculty Collaboration Database

Hsp90-Akt phosphorylates ASK1 and inhibits ASK1-mediated apoptosis. Oncogene 2005 Jun 02;24(24):3954-63

Date

03/23/2005

Pubmed ID

15782121

DOI

10.1038/sj.onc.1208548

Scopus ID

2-s2.0-20544446881 (requires institutional sign-in at Scopus site)   156 Citations

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 (H(2)O(2))-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 H(2)O(2), 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.

Author List

Zhang R, Luo D, Miao R, Bai L, Ge Q, Sessa WC, Min W

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Cattle
Cells, Cultured
Endothelium, Vascular
Genes, Reporter
HSP90 Heat-Shock Proteins
Humans
MAP Kinase Kinase Kinase 5
Mutagenesis, Site-Directed
Phosphorylation
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-akt
Transfection
Umbilical Veins