Akt phosphorylates the TR3 orphan receptor and blocks its targeting to the mitochondria
Abstract
Acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt) phosphorylates and regulates the function of many cellular proteins involved in processes such as metabolism, apoptosis and proliferation. However, the precise mechanisms by which Akt promotes cell survival and inhibits apoptosis have been characterized in part only. TR3, an orphan receptor, functions as a transcription factor that can both positively or negatively regulate gene expression. We have reported previously that the translocation of TR3 from the nucleus to the mitochondria can elicit a proapoptotic effect in gastric cancer cells. In our present study, we demonstrate that Akt phosphorylates cytoplasmic TR3 through its physical interaction with the N-terminus of TR3. When coexpressed with Akt, TR3 mitochondrial targeting was blocked and this protein adopted a diffuse expression pattern in the cytoplasm. Moreover, Akt displayed an ability to disrupt the interaction of TR3 with Bcl-2, which is thought to be a critical requirement for mitochondrial TR3 to elicit apoptosis. Consistently, insulin was also found to induce the phosphorylation of TR3 and abolish 12-O-tetradecanoylphorbol-13-acetate-induced mitochondrial localization, which was dependent upon ...Continue Reading
References
Identification of a new member of the steroid receptor super-family by cloning and sequence analysis
Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3
The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes.
p53 and Nur77/TR3 - transcription factors that directly target mitochondria for cell death induction
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