Kaiso phosphorylation at threonine 606 leads to its accumulation in the cytoplasm, reducing its transcriptional repression of the tumour suppressor CDH1

It is well known that the Kaiso protein (encoded by the ZBTB33 gene) is a transcription factor, and Kaiso–P120ctn [P120 catenin (CTNND1)] interaction increases the translocation of Kaiso from the nucleus into the cytoplasm. However, the regulatory mechanisms of Kaiso compartmentalisation are far from clear. Here, we reported that RAC‐alpha serine/threonine‐protein kinase (AKT1) could phosphorylate threonine residue 606 (T606) within the RSSTIP motif of Kaiso in the cytoplasm. The T606‐phosphorylated Kaiso (pT606‐Kaiso) could directly bind to 14‐3‐3 family proteins, and depletion of T606 phosphorylation by T606A mutation abolished most of the Kaiso–14‐3‐3 binding. In addition, the Kaiso–P120ctn interaction was essential for pT606‐Kaiso accumulation in the cytoplasm. Notably, enforced stratifin (14‐3‐3σ; SFN) overexpression could increase pT606‐Kaiso accumulation in the cytoplasm and de‐repress the transcription of Kaiso target gene cadherin 1 (CDH1), which is a tumour suppressor. Decreased amounts of both pT606‐Kaiso and CDH1 proteins were frequently observed in human gastric cancer tissues compared to paired normal controls. The mRNA levels of 14‐3‐3σ and Kaiso target gene CDH1 showed highly significant positive correlations in both human normal tissues and cancer cell lines by bioinformatics analyses. Furthermore, Kaiso T606A mutant (unable to be phosphorylated) significantly increased the migration and invasion of cancer cells in vitro and promoted the growth of these cells in vivo. In conclusion, Kaiso could be phosphorylated at T606 by AKT1 and pT606‐Kaiso accumulates in the cytoplasm through binding to 14‐3‐3/P120ctn, which de‐represses the Kaiso target gene CDH1 in normal tissues. Decreased Kaiso phosphorylation might contribute to the development of gastrointestinal cancer. The status of Kaiso phosphorylation is a determinant factor for the role of Kaiso in the development of cancer.