Akt Forms an Intracellular Complex with Heat Shock Protein 90 (Hsp90) and Cdc37 and Is Destabilized by Inhibitors of Hsp90 Function*

By A. Basso, D. Solit, G. Chiosis, Banabihari Giri, P. Tsichlis, N. Rosen. Journal of Biological Chemistry, 2002

631 citations recorded by the source corpus.

Hsp90 is a chaperone required for the conformational maturation of certain signaling proteins including Raf, cdk4, and steroid receptors. Natural products and synthetic small molecules that bind to the ATP-binding pocket in the amino-terminal domain of Hsp90 inhibit its function and cause the degradation of these client proteins. Inhibition of Hsp90 function in cells causes down-regulation of an Akt kinase-dependent pathway required for D-cyclin expression and retinoblastoma protein-dependent G1 arrest. Intracellular Akt is associated with Hsp90 and Cdc37 in a complex in which Akt kinase is active and regulated by phosphatidylinositol 3-kinase. Functional Hsp90 is required for the stability of Akt in the complex. Occupancy of the ATP-binding pocket by inhibitors is associated with the ubiquitination of Akt and its targeting to the proteasome, where it is degraded. This results in a shortening of the half-life of Akt from 36 to 12 h and an 80% reduction in its expression. Akt and its activating kinase, PDK1, are the only members of the protein kinase A/protein kinase B/protein kinase C-like kinase family that are affected by Hsp90 inhibitors. Thus, transduction of growth factor signaling via the Akt and Raf pathways requires functional Hsp90 and can be coordinately blocked by its inhibition.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5e1098379f4680d3ef9669d0068212788ba9ebb7

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Citations in the corpus

`The stress of dying': the role of heat shock proteins in the regulation of apoptosis (2004, background): “Chen et al. reported that IKK forms a complex with Hsp90 and Cdc37 (Chen et al., 2002) – a cochaperone that binds cooperatively with Hsp90 to regulate signal transduction (Kimura et al., 1997; Septanova et al., 1996).”
PI3K/Akt and apoptosis: size matters (2003, background): “First, the extracellular factors that trigger the intracellular activation of Akt may be increased or the receptors that receive their signals may be altered or present in increased numbers (Bacus et al., 2002; Basso et al., 2002; Munster et al., 2002; Pianetti et al., 2002; Salh et al., 2002).”
HSP90 and the chaperoning of cancer (2005, background): “Much of this activity seems to be mediated through effects on AK”
PI3K/Akt: getting it right matters (2008, background): “Heat shock protein 90 (HSP90) (Basso et al., 2002), tribbles homolog 3 (TRB3) (Du et al.”
Functional proteomic screens reveal an essential extracellular role for hsp90α in cancer cell invasiveness (2004, background): “GA-beads had no effect on intracellular functions of hsp90, such as Akt phosphorylatio”