Protein-tyrosine Phosphatase PCP-2 Inhibits β-Catenin Signaling and Increases E-cadherin-dependent Cell Adhesion

• Published in: The Journal of biological chemistry 2006-06, Vol.281 (22), p.15423-15433
• Main Authors: Yan, He-Xin, Yang, Wen, Zhang, Rui, Chen, Lei, Tang, Liang, Zhai, Bo, Liu, Shu-Qin, Cao, Hui-Fang, Man, Xiao-Bo, Wu, Hong-Ping, Wu, Meng-Chao, Wang, Hong-Yang
• Format: Article
• Language: English
• Subjects: Base Sequence; beta Catenin - antagonists & inhibitors; beta Catenin - metabolism; Cadherins - metabolism; Cell Adhesion - physiology; Cell Line; Cell Proliferation; Cytoplasm - metabolism; Genes, myc; Humans; Membranes - metabolism; Mutagenesis, Site-Directed; Phosphorylation; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA, Small Interfering - genetics; Signal Transduction; Transcriptional Activation; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M602607200

β-Catenin is a key molecule involved in both cell adhesion and Wnt signaling pathway. However, the exact relationship between these two roles has not been clearly elucidated. Tyrosine phosphorylation of β-catenin was shown to decrease its binding to E-cadherin, leading to decreased cell adhesion and increased β-catenin signaling. We have previously shown that receptor-like protein-tyrosine phosphatase PCP-2 localizes to the adherens junctions and directly binds and dephosphorylates β-catenin, suggesting that PCP-2 might regulate the balance between signaling and adhesive β-catenin. Here we demonstrate that PCP-2 can inhibit both the wild-type and constitutively active forms of β-catenin in activating target genes such as c-myc. The phosphatase activity of PCP-2 is required for this effect since loss of catalytic activity attenuates its inhibitory effect on β-catenin activation. Expression of PCP-2 in SW480 colon cancer cells can lead to stabilization of cytosolic pools of β-catenin perhaps, by virtue of their physical interaction. PCP-2 expression also leads to increased membrane-bound E-cadherin and greater stabilization of adherens junctions by dephosphorylation of β-catenin, which could further sequester cytosolic β-catenin and thus inhibit β-catenin mediated nuclear signaling. Furthermore, SW480 cells stably expressing PCP-2 have a reduced ability to proliferate and migrate. Thus, PCP-2 may play an important role in the maintenance of epithelial integrity, and a loss of its regulatory function may be an alternative mechanism for activating β-catenin signaling.