p120-catenin regulates E-cadherin stability at the plasma membrane as well as Rho GTPase activity in the cyto­plasm, and also interacts with the transcriptional repressor, Kaiso, in the nucleus. However, the role of different isoforms and the phosphorylated state of p120-catenin in the nucleus is poorly understood. In the present study, we show that p120-catenin isoform 3 interacts with Kaiso in lung cancer cells by immunoprecipitation. Nuclear-cytoplasmic extraction and immunofluoresence confirmed that Kaiso shuttled out of the nucleus via p120-catenin isoform 3. The cytoplasmic enrichment of Kaiso by p120-catenin isoform 3 was abolished due to the inhibition of chromosomal region maintenance-dependent nuclear export via leptomycin. The lung tumor tissue and cell lines expressed higher levels of the serine 288 phosphorylated form. Also, serine 288 phosphorylation in p120-catenin isoform 3 enhanced the binding with Kaiso. Moreover, immuno­fluoresence and transwell invasion assay showed that the phosphorylation of serine and threonine sites in p120-catenin induced F-actin remodelling and promoted the invasion of lung cancer cells. Collectively, our data establish that p120-catenin isoform 3 regulates the nuclear export of Kaiso and promotes invasion in lung cancer cells via a phosphorylation-dependent mechanism. Serine 288 phosphorylation can contribute to lung cancer progression.

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