Regulation of Akt expression and signaling by the Hsp90 chaperone

Heat Shock Protein 90 (Hsp90) is a protein chaperone required for the conformational maturation of a subset of signaling proteins, including steroid receptors, the Raf serine kinase, and certain tyrosine kinases. An ATP-binding site in its amino terminal domain is required for its function. Natural products such as ansamycins that occupy this pocket cause the degradation of Hsp90 client proteins followed by G1 cell cycle arrest and subsequent differentiation and apoptosis of cancer cells. The G1 arrest is retinoblastoma protein (RB)-dependent and associated with downregulation of D-cyclin/cdk4 activity. Cyclin dependent kinase 4 (cdk4) is a direct target of these inhibitors, whereas they also downregulate a phosphatidyl inositol 3′ kinase (PI3k)/Akt-dependent pathway required for D-cyclin expression. The mechanism of inhibition of the P13k/Akt pathway was complex. Akt was present in a cytosolic complex containing Cdc37 and Hsp90. Neither growth factor-induced activation of Akt kinase nor Hsp90 inhibitors affected association of Akt with the complex, but the latter caused the ubiquitin-dependent degradation of Akt in the proteasome. Akt kinase activity fell in parallel with protein expression in most cell lines. In addition, in tumors in which an Hsp90-client protein is responsible for Akt activation, Hsp90 inhibitors down regulated Akt kinase independently of their effect of Akt protein expression. For example, in HER2-overexpressing breast cancer cells, Hsp90 inhibitors caused HER2 degradation, concomitant loss of HER3 phospliorylation and association with PI3 kinase and loss of Akt activity. In these cells, inhibition of Akt activation leads to a decline in Cyclin D expression, apoptosis, and sensitization to paclitaxel. Thus, Hsp90 inhibitors may be useful in treating the many tumors that depend upon aberrant activation of the Akt pathway.