T606-phosphorylation deprives the function of Kaiso as a transcription repressor

It is well known that Kaiso protein encoded by ZBTB33 gene is a transcription repressor and that Kaiso-P120ctn interaction increases the shift of Kaiso from the nucleus into the cytoplasm. However, the regulatory mechanisms of Kaiso compartmentalization are far from clear. Here, we reported that AKT1 could phosphorylate 606-threonine residue (T606) within the RSSTIP motif of Kaiso in the cytoplasm. The pT606-Kaiso could directly bind to 14-3-3 family proteins and the loss of T606 phosphorylation by T606A mutation abolished most of the Kaiso-14-3-3 binding. In addition, the Kaiso-P120ctn interaction was essential for the pT606-Kaiso accumulation in the cytoplasm. Notably, enforced 14-3-3 Sigma (SFN) overexpression could increase the pT606-Kaiso accumulation in the cytoplasm and de-repress the transcription of Kaiso target genes, including CDH1. Decreased amounts of both T606-phosphorylated Kaiso (pT606-Kaiso) and CDH1 were frequently observed in human gastric and colon cancer tissues relative to paired normal controls. The mRNA levels of 14-3-3 Sigma and Kaiso target gene CDH1 were positively and significantly correlated with each other in bioinformatics analyses using publicly available RNA-seq datasets for human normal tissues (n=11688, r=0.60, p