Modulation of Akt kinase activity by binding to Hsp90

TLDR

Akt/PKB is a downstream effector of PI3K that mediates many anti‑apoptotic responses. Deletion mutants mapped the Akt–Hsp90 interaction to Akt residues 229–309 and Hsp90β residues 327–340. Akt binds Hsp90 in vivo, and disrupting this complex triggers PP2A‑mediated dephosphorylation that inactivates Akt and increases apoptosis sensitivity, showing Hsp90 protects Akt activity.

Abstract

Serine/threonine kinase Akt/PKB is a downstream effector molecule of phosphoinositide 3-kinase and is thought to mediate many biological actions toward anti-apoptotic responses. We found that Akt formed a complex with a 90-kDa heat-shock protein (Hsp90) in vivo . By constructing deletion mutants, we identified that amino acid residues 229–309 of Akt were involved in the binding to Hsp90 and amino acid residues 327–340 of Hsp90β were involved in the binding to Akt. Inhibition of Akt-Hsp90 binding led to the dephosphorylation and inactivation of Akt, which increased sensitivity of the cells to apoptosis-inducing stimulus. The dephosphorylation of Akt was caused by an increase in protein phosphatase 2A (PP2A)-mediated dephosphorylation and not by a decrease in 3-phosphoinositide-dependent protein kinase-1-mediated phosphorylation. These results indicate that Hsp90 plays an important role in maintaining Akt kinase activity by preventing PP2A-mediated dephosphorylation.