Journal
MOLECULAR CELL
Volume 36, Issue 4, Pages 547-559Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2009.09.034
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Funding
- American Cancer Society Research Scholar Award [RSG-09-277-01-CSM]
- Brain Tumor Society research grant
- Phi Beta Psi Sorority research grant
- University of Texas M.D. Anderson Cancer Center
- National Cancer Institute [5R01 CA109035]
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Increased transcriptional activity of beta-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 beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via CK2 alpha-dependent phosphorylation of alpha-catenin at S641. ERK2, which is activated by EGFR signaling, directly binds to CK2 alpha via the ERK2 docking groove and phosphorylates CK2 alpha primarily at T360/S362, subsequently enhancing CK2 alpha activity toward alpha-catenin phosphorylation. In addition, levels of alpha-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 alpha-catenin promotes beta-catenin transactivation and tumor cell invasion. These findings highlight the importance of the crosstalk between EGFR and Writ pathways in tumor development.
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