Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Division of Cancer Etiology, Peking University Cancer Hospital and Institute, Beijing, China.
Mol Oncol. 2022 Sep;16(17):3192-3209. doi: 10.1002/1878-0261.13292. Epub 2022 Jul 28.
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.
众所周知，Kaiso 蛋白（由 ZBTB33 基因编码）是一种转录因子，Kaiso-P120ctn[P120 连接蛋白（CTNND1）]相互作用增加 Kaiso 从核内易位到细胞质。然而，Kaiso 区室化的调节机制还远不清楚。在这里，我们报道 RAC-alpha 丝氨酸/苏氨酸蛋白激酶（AKT1）可以在细胞质中 Kaiso 的 RSSTIP 基序内磷酸化苏氨酸残基 606（T606）。磷酸化的 Kaiso（pT606-Kaiso）可以直接与 14-3-3 家族蛋白结合，并且通过 T606A 突变耗尽 T606 磷酸化会使 Kaiso-14-3-3 结合大部分丧失。此外，Kaiso-P120ctn 相互作用对于 pT606-Kaiso 在细胞质中的积累是必需的。值得注意的是，强制 stratifin（14-3-3σ；SFN）过表达可以增加细胞质中 pT606-Kaiso 的积累并解除 Kaiso 靶基因钙粘蛋白 1（CDH1）的转录抑制，CDH1 是一种肿瘤抑制因子。与配对的正常对照相比，在人胃癌组织中经常观察到 pT606-Kaiso 和 CDH1 蛋白的含量均减少。通过生物信息学分析，在人正常组织和癌细胞系中，14-3-3σ 和 Kaiso 靶基因 CDH1 的 mRNA 水平显示出高度显著的正相关。此外，Kaiso T606A 突变体（不能被磷酸化）在体外显著增加了癌细胞的迁移和侵袭，并促进了这些细胞在体内的生长。总之，Kaiso 可以被 AKT1 在 T606 处磷酸化，并且通过与 14-3-3/P120ctn 结合，pT606-Kaiso 在细胞质中积累，从而解除正常组织中 Kaiso 靶基因 CDH1 的转录抑制。Kaiso 磷酸化的减少可能有助于胃肠道癌症的发展。Kaiso 磷酸化的状态是 Kaiso 在癌症发展中作用的决定因素。
