title: Phosphorylation accelerates geldanamycin-induced Akt degradation.
abstract: 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.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Su
authors.forename: Keng-Hsin
authors.initials: KH
authors.lastname: Lan
authors.forename: Chung-Pin
authors.initials: CP
authors.lastname: Li
authors.forename: Yee
authors.initials: Y
authors.lastname: Chao
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Lee
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects*; D017354:Point Mutation; D059748:Proteolysis / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; C001277:geldanamycin
keywords: Akt; CHIP; Hsp90 inhibitor; Phosphorylation