The E3 ligase TTC3 facilitates ubiquitination and degradation of phosphorylated Akt.
The serine threonine kinase Akt is a core survival factor that underlies a variety of human diseases. Although regulatory phosphorylation and dephosphorylation have been well documented, the other posttranslational mechanisms that modulate Akt activity remain unclear. We show here that tetratricopeptide repeat domain 3 (TTC3) is an E3 ligase that interacts with Akt. TTC3 contains a canonical RING finger motif, a pair of tetratricopeptide motifs, a putative Akt phosphorylation site, and nuclear localization signals, and is encoded by a gene within the Down syndrome (DS) critical region on chromosome 21. TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus. Moreover, DS cells exhibit elevated TTC3 expression, reduced phosphorylated Akt, and accumulation in the G(2)M phase, which can be reversed by TTC3 siRNA or Myr-Akt. Thus, interaction between TTC3 and Akt may contribute to the clinical symptoms of DS.
Suizu
Futoshi
F
Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Hiramuki
Yosuke
Y
Okumura
Fumihiko
F
Matsuda
Mami
M
Okumura
Akiko J
AJ
Hirata
Noriyuki
N
Narita
Masumi
M
Kohno
Takashi
T
Yokota
Jun
J
Bohgaki
Miyuki
M
Obuse
Chikashi
C
Hatakeyama
Shigetsugu
S
Obata
Toshiyuki
T
Noguchi
Masayuki
M
D002460:Cell Line; D002478:Cells, Cultured; D004314:Down Syndrome / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025941:Protein Interaction Mapping; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
C108062:TTC3 protein, human; D044767:Ubiquitin-Protein Ligases; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex