C-Src-mediated phosphorylation of δ-catenin increases its protein stability and the ability of inducing nuclear distribution of β-catenin.

Although δ-catenin was first considered as a brain specific protein, strong evidence of δ-catenin overexpression in various cancers, including prostate cancer, has been accumulated. Phosphorylation of δ-catenin by Akt and GSK3β has been studied in various cell lines. However, tyrosine phosphorylation of δ-catenin in prostate cancer cells remains unknown. In the current study, we demonstrated that Src kinase itself phosphorylates δ-catenin on its tyrosine residues in prostate cancer cells and further illustrated that Y1073, Y1112 and Y1176 of δ-catenin are predominant sites responsible for tyrosine phosphorylation mediated by c-Src. Apart from c-Src, other Src family kinases, including Fgr, Fyn and Lyn can also phosphorylate δ-catenin. We also found that c-Src-mediated Tyr-phosphorylation of δ-catenin increases its stability via decreasing its affinity to GSK3β and enhances its ability of inducing nuclear distribution ofβ-catenin through interrupting the integrity of the E-cadherin. Taken together, these results indicate c-Src can enhance the oncogenic function of δ-catenin in prostate cancer cells.

尽管δ-连环蛋白最初被认为是一种脑特异性蛋白，但在包括前列腺癌在内的多种癌症中δ-连环蛋白过度表达的有力证据已不断积累。在多种细胞系中已经研究了Akt和GSK3β对δ-连环蛋白的磷酸化作用。然而，前列腺癌细胞中δ-连环蛋白的酪氨酸磷酸化情况仍然未知。在本研究中，我们证明了Src激酶自身可使前列腺癌细胞中δ-连环蛋白的酪氨酸残基磷酸化，并进一步阐明了δ-连环蛋白的Y1073、Y1112和Y1176是c - Src介导的酪氨酸磷酸化的主要位点。除了c - Src，其他Src家族激酶，包括Fgr、Fyn和Lyn也可使δ-连环蛋白磷酸化。我们还发现c - Src介导的δ-连环蛋白的酪氨酸磷酸化通过降低其与GSK3β的亲和力增加了其稳定性，并通过破坏E -钙黏蛋白的完整性增强了其诱导β-连环蛋白核分布的能力。综上所述，这些结果表明c - Src可增强δ-连环蛋白在前列腺癌细胞中的致癌功能。