Regulation of E-cadherin/Catenin Association by Tyrosine Phosphorylation

Abstract

Alteration of cadherin-mediated cell-cell adhesion is frequently associated to tyrosine phosphorylation of p120-and ␤-catenins. We have examined the role of this modification in these proteins in the control of ␤-catenin/E-cadherin binding using in vitro assays with recombinant proteins. Recombinant pp60 c-src efficiently phosphorylated both catenins in vitro, with stoichiometries of 1.5 and 2.0 mol of phosphate/mol of protein for ␤-catenin and p120-catenin, respectively. pp60 c-src phosphorylation had opposing effects on the affinities of ␤-catenin and p120 for the cytosolic domain of E-cadherin; it decreased (in the case of ␤-catenin) or increased (for p120) catenin/E-cadherin binding. However, a role for p120-catenin in the modulation of ␤-catenin/E-cadherin binding was not observed, since addition of phosphorylated p120-catenin did not modify the affinity of phosphorylated (or unphosphorylated) ␤-catenin for E-cadherin. The phosphorylated Tyr residues were identified as Tyr-86 and Tyr-654. Experiments using point mutants in these two residues indicated that, although Tyr-86 was a better substrate for pp60 c-src , only modification of Tyr-654 was relevant for the interaction with E-cadherin. Transient transfections of different mutants demonstrated that Tyr-654 is phosphorylated in conditions in which adherens junctions are disrupted and evidenced that binding of ␤-catenin to E-cadherin in vivo is controlled by phosphorylation of ␤-catenin Tyr-654.

Cytoplasmic localization of p120ctn and E-cadherin loss characterize lobular breast carcinoma from preinvasive to metastatic lesions

“…Although we have not evaluated the phosphorylation status of p120, we found that the mean value of Src activity was higher in IDC with preserved p120 or E-CD expression than in those with reduced p120 or E-CD expression, thus implying that increased Src activity is not associated with a reduction in E-CD or p120. Our results are in accordance with previous experimental evidence that indicates that Src-induced p120 tyrosine phosphorylation increased its affinity for E-CD (Roura et al, 1999). As mentioned above, lobular tumors lack E-CD and b-catenin expression but accumulate p120 in the cytoplasm.…”

Muc1 affects c-Src signaling in PyV MT-induced mammary tumorigenesis

“…The presence of Muc1 in MT-induced tumors promoted the association between c-Src and b-catenin. Tyrosine phosphorylation of b-catenin by c-Src at Y654 has been shown to disrupt the binding of b-catenin to E-cadherin (Roura et al, 1999). However, analysis of tumors from MT and MTK mice did not reveal a substantial change in the amount of b-catenin in association with Ecadherin, suggesting an alternate mechanism for weakening cadherin-dependent adhesions in PyV MT tumors.…”

Gastrin-mediated activation of cyclin D1 transcription involves β-catenin and CREB pathways in gastric cancer cells

“…A recent study with MDCK kidney cells showed a gastrin-induced decrease in E-cadherin and b-catenin interaction (Bierkamp et al, 2002). Since tyrosine phosphorylation of b-catenin can modulate E-cadherin/b-catenin interaction Roura et al, 1999), it is possible that gastrin modulates b-catenin activity via modulating its tyrosine phosphorylation. In fact, studies by Hollande et al (2001), showed an increase in b-catenin tyrosine phosphorylation by G-17-Gly, although it is unclear whether a similar mechanism is activated by G-17 as well.…”