Phosphorylation accelerates geldanamycin-induced Akt degradation

Arch Biochem Biophys. 2013 Aug 1;536(1):6-11. doi: 10.1016/ Epub 2013 May 10.


Hsp90 (Heat shock protein-90) is a cellular buffer against erroneous gene products and also plays an essential role in facilitating proper folding, maturation, and activity of its client proteins. The phosphatidylinositol-3 kinase (PI-3K)-Akt pathway transduces a survival signal involved in tumor development. The kinase activity of Akt depends on its association with Hsp90. Hsp90 inhibition causes Akt degradation, but the mechanism remains unclear. Several reports showed that the Hsp90 inhibitor geldanamycin (GA) induces Thr308 and Ser473 phosphorylations of Akt, however, it is still unknown about the significance of GA-induced Akt activation in degradation of the kinase. We treated Hela cells with GA to observe Akt degradation and found that LY294002 delayed Akt degradation. Mutation of Thr308 or Ser473 also caused delayed Akt ubiquitination and degradation. Inhibition of Akt dephosphorylation enhanced GA-mediated Akt degradation. In this report, we show that GA-mediated transient activation of Akt accelerates its association with the E3 ligase CHIP (C-terminal Hsp70-interacting protein)-mediated ubiquitination and subsequent proteasome degradation.

Keywords: Akt; CHIP; Hsp90 inhibitor; Phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Benzoquinones / pharmacology*
  • Enzyme Activation / drug effects
  • HEK293 Cells
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • HeLa Cells
  • Humans
  • Lactams, Macrocyclic / pharmacology*
  • Mice
  • Phosphorylation / drug effects*
  • Point Mutation
  • Proteolysis / drug effects*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / drug effects


  • Antibiotics, Antineoplastic
  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • STUB1 protein, human
  • Ubiquitin-Protein Ligases
  • Proto-Oncogene Proteins c-akt
  • geldanamycin