The E3 Ligase TTC3 Facilitates Ubiquitination and Degradation of Phosphorylated Akt

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 post-translational mechanisms that modulate Akt activity remain unclear. We show herein that TTC3 (tetratricopeptide repeat domain 3) is an E3 ligase that interacts with Akt. TTC3 contains a canonical RING-finger motif, a pair of TPR (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 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