Modulation of Akt Kinase Activity by Binding to Hsp90

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 20; pp. 10832 - 10837
• Main Authors: Sato, Saori, Fujita, Naoya, Tsuruo, Takashi
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 26.09.2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Amino acids; Antibodies; Apoptosis; Biological Sciences; Biotechnology; Cell Line; Cellular biology; Cellular immunity; Complementary DNA; Cultured cells; Enzyme Activation; HSP90 Heat-Shock Proteins - metabolism; Humans; Mutation; Phosphatases; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Protein Binding; Protein-Serine-Threonine Kinases - metabolism; Proteins; Signal Transduction; Transfection
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.170276797

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.