EGF-Induced ERK Activation Promotes CK2-Mediated Disassociation of α-Catenin from β-Catenin and Transactivation of β-Catenin

Increased transcriptional activity of β-catenin resulting from Wnt/Wingless-dependent or -independent signaling has been detected in many types of human cancer, but the underlying mechanism of Wnt-independent regulation remains unclear. We demonstrate here that EGFR activation results in disruption of the complex of β-catenin and α-catenin, thereby abrogating the inhibitory effect of α-catenin on β-catenin transactivation via CK2α-dependent phosphorylation of α-catenin at S641. ERK2, which is activated by EGFR signaling, directly binds to CK2α via the ERK2 docking groove and phosphorylates CK2α primarily at T360/S362, subsequently enhancing CK2α activity toward α-catenin phosphorylation. In addition, levels of α-catenin S641 phosphorylation correlate with levels of ERK1/2 activity in human glioblastoma specimens and with grades of glioma malignancy. This EGFR-ERK-CK2-mediated phosphorylation of α-catenin promotes β-catenin transactivation and tumor cell invasion. These findings highlight the importance of the crosstalk between EGFR and Wnt pathways in tumor development.