The E3 Ligase TTC3 Facilitates Ubiquitination and Degradation of Phosphorylated Akt

Futoshi Suizu, Yosuke Hiramuki, Fumihiko Okumura, Mami Matsuda, Akiko J. Okumura, Noriyuki Hirata, Masumi Narita, Takashi Kohno, Jun Yokota, Miyuki Bohgaki, Chikashi Obuse, Shigetsugu Hatakeyama, Toshiyuki Obata, Masayuki Noguchi

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Abstract

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 G2M 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.

Original languageEnglish
Pages (from-to)800-810
Number of pages11
JournalDevelopmental Cell
Volume17
Issue number6
DOIs
Publication statusPublished - Dec 15 2009
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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