Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function Journal Article
| Authors: | Basso, A. D.; Solit, D. B.; Chiosis, G.; Giri, B.; Tsichlis, P.; Rosen, N. |
| Article Title: | Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function |
| Abstract: | 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. |
| Keywords: | signal transduction; protein kinase b; controlled study; unclassified drug; human cell; proto-oncogene proteins; raf protein; protein conformation; protein function; proteins; cell cycle protein; animals; cell cycle proteins; mice; complex formation; proteasome; enzyme inhibition; proteasome endopeptidase complex; benzyloxycarbonylleucylleucylleucinal; protein degradation; protein protein interaction; protein binding; protein stability; down-regulation; antineoplastic activity; cancer cell culture; tumor cells, cultured; phosphorylation; phosphatidylinositol 3 kinase; mice, inbred balb c; time factors; amino terminal sequence; drug mechanism; protein-serine-threonine kinases; proto-oncogene proteins c-akt; immunoblotting; heat shock protein 90; hsp90 heat-shock proteins; binding site; microscopy, fluorescence; protein structure, tertiary; protein kinase c; down regulation; adenosine triphosphate; protein family; multienzyme complexes; half life time; steroid receptors; biochemistry; steroid receptor; drosophila proteins; cell cycle g1 phase; drug protein binding; protein inhibitor; cyclin dependent kinase 4; 2 morpholino 8 phenylchromone; protein modification; geldanamycin; radicicol; cyclic amp dependent protein kinase; cyclic amp-dependent protein kinases; cells; degradation; molecular chaperones; mitosis inhibition; cell cycle protein 37; cysteine endopeptidases; chaperonins; humans; human; female; priority journal; article |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 277 |
| Issue: | 42 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2002-10-18 |
| Start Page: | 39858 |
| End Page: | 39866 |
| Language: | English |
| DOI: | 10.1074/jbc.M206322200 |
| PUBMED: | 12176997 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 14 November 2014 -- Source: Scopus |
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