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J. Biol. Chem., Vol. 277, Issue 42, 39858-39866, October 18, 2002
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From the 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.
Akt Forms an Intracellular Complex with Heat Shock
Protein 90 (Hsp90) and Cdc37 and Is Destabilized by Inhibitors of Hsp90
Function*
§,§
Program in Pharmacology, Weill Graduate
School of Medical Sciences, Cornell University and the
§ Program in Cell Biology and Department of Medicine,
Memorial Sloan-Kettering Cancer Center, New York, New York 10021 and
the ¶ Kimmel Cancer Center, Thomas Jefferson University,
Philadelphia, Pennsylvania 19107
*
This work was supported in part by National Cancer Institute
Grant P50CA9262901, U01CA91178, National Institutes of Health Grant
R01 CA57436, Susan Komen Grant F32, and generously by the Taub
Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Program in Cell
Biology, Memorial Sloan-Kettering Cancer Center, Box 271, 1275 York
Ave., New York, NY 10021. Tel.: 212-639-2369; Fax: 212-717-3627; E-mail: rosenn@mskcc.org.
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
O. M. Grbovic, A. D. Basso, A. Sawai, Q. Ye, P. Friedlander, D. Solit, and N. Rosen V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors PNAS, January 3, 2006; 103(1): 57 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
T. Shimamura, A. M. Lowell, J. A. Engelman, and G. I. Shapiro Epidermal Growth Factor Receptors Harboring Kinase Domain Mutations Associate with the Heat Shock Protein 90 Chaperone and Are Destabilized following Exposure to Geldanamycins Cancer Res., July 15, 2005; 65(14): 6401 - 6408. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Song and Y. J. Lee Dissociation of Akt1 from its negative regulator JIP1 is mediated through the ASK1-MEK-JNK signal transduction pathway during metabolic oxidative stress: a negative feedback loop J. Cell Biol., July 4, 2005; 170(1): 61 - 72. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Katayama, N. Fujita, and T. Tsuruo Akt/Protein Kinase B-Dependent Phosphorylation and Inactivation of WEE1Hu Promote Cell Cycle Progression at G2/M Transition Mol. Cell. Biol., July 1, 2005; 25(13): 5725 - 5737. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Mesa, D. Loegering, H. L. Powell, K. Flatten, S. J. H. Arlander, N. T. Dai, M. P. Heldebrant, B. T. Vroman, B. D. Smith, J. E. Karp, et al. Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine Blood, July 1, 2005; 106(1): 318 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Medina, R. R. Afsari, T. Ravid, S. S. Castillo, K. L. Erickson, and T. Goldkorn Tumor Necrosis Factor-{alpha} Decreases Akt Protein Levels in 3T3-L1 Adipocytes via the Caspase-Dependent Ubiquitination of Akt Endocrinology, June 1, 2005; 146(6): 2726 - 2735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Wei and Y. Xia Roles of 3-Phosphoinositide-dependent Kinase 1 in the Regulation of Endothelial Nitric-oxide Synthase Phosphorylation and Function by Heat Shock Protein 90 J. Biol. Chem., May 6, 2005; 280(18): 18081 - 18086. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Anai, N. Shojima, H. Katagiri, T. Ogihara, H. Sakoda, Y. Onishi, H. Ono, M. Fujishiro, Y. Fukushima, N. Horike, et al. A Novel Protein Kinase B (PKB)/AKT-binding Protein Enhances PKB Kinase Activity and Regulates DNA Synthesis J. Biol. Chem., May 6, 2005; 280(18): 18525 - 18535. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
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|
|
|
|
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|
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|
|
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