Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function

Andrea D. Basso, David B. Solit, Gabriela Chiosis, Banabihari Giri, Philip Tsichlis, Neal Rosen

Research output: Contribution to journalArticle

489 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)39858-39866
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number42
DOIs
StatePublished - Oct 18 2002

Fingerprint

HSP90 Heat-Shock Proteins
Phosphotransferases
Adenosine Triphosphate
Phosphatidylinositol 3-Kinase
Cyclin D
Retinoblastoma Protein
Proto-Oncogene Proteins c-akt
Steroid Receptors
Ubiquitination
Proteasome Endopeptidase Complex
Cyclic AMP-Dependent Protein Kinases
Biological Products
Protein Kinase C
Proteolysis
Half-Life
Intercellular Signaling Peptides and Proteins
Proteins
Down-Regulation
Degradation
Molecules

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. / Basso, Andrea D.; Solit, David B.; Chiosis, Gabriela; Giri, Banabihari; Tsichlis, Philip; Rosen, Neal.

In: Journal of Biological Chemistry, Vol. 277, No. 42, 18.10.2002, p. 39858-39866.

Research output: Contribution to journalArticle

Basso, Andrea D. ; Solit, David B. ; Chiosis, Gabriela ; Giri, Banabihari ; Tsichlis, Philip ; Rosen, Neal. / Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 42. pp. 39858-39866.
@article{08b2ac1a0dde4700a0b3dd7441f1daec,
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.",
author = "Basso, {Andrea D.} and Solit, {David B.} and Gabriela Chiosis and Banabihari Giri and Philip Tsichlis and Neal Rosen",
year = "2002",
month = "10",
day = "18",
doi = "10.1074/jbc.M206322200",
language = "English (US)",
volume = "277",
pages = "39858--39866",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "42",

}

TY - JOUR

T1 - Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function

AU - Basso, Andrea D.

AU - Solit, David B.

AU - Chiosis, Gabriela

AU - Giri, Banabihari

AU - Tsichlis, Philip

AU - Rosen, Neal

PY - 2002/10/18

Y1 - 2002/10/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0037131187&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037131187&partnerID=8YFLogxK

U2 - 10.1074/jbc.M206322200

DO - 10.1074/jbc.M206322200

M3 - Article

C2 - 12176997

AN - SCOPUS:0037131187

VL - 277

SP - 39858

EP - 39866

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 42

ER -