title: Akt phosphorylation at Thr308 and Ser473 is required for CHIP-mediated ubiquitination of the kinase.
abstract: Phosphorylation at Thr308 and Ser473 is known to activate Akt, a major kinase in mammalian cells. Once activated to turn on downstream signaling pathways, Akt returns to an inactive pool via PP2A-mediated dephosphorylation. We show here that Thr308 and Ser473 phosphorylations prompt Akt to enter the CHIP-mediated ubiquitin-proteasome pathway. Mutation at either Thr308 or Ser473 dampened its ability to bind to the U-box E3 ligase CHIP (C-terminal Hsp70 -interacting protein), and the Akt mutants revealed decreased rate of ubiquitination by CHIP. Our study unveils that the well-known phosphorylations responsible for Akt activation turn out to transduce recognition signals for Akt-CHIP binding and ensuing 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: Cheng-Yi
authors.initials: CY
authors.lastname: Wang
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; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D010766:Phosphorylation / Q000235:genetics; D010957:Plasmids; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D013912:Threonine / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics; D018832:Molecular Chaperones
chemical_list: D002352:Carrier Proteins; D046988:Proteasome Endopeptidase Complex; D054648:Protein Phosphatase 2; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D013912:Threonine; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; C101119:ST13 protein, human; D018832:Molecular Chaperones