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...

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Bibliographic Details
Published in:Molecular cell 2009-11, Vol.36 (4), p.547-559
Main Authors: Ji, Haitao, Wang, Ji, Nika, Heinz, Hawke, David, Keezer, Susan, Ge, Qingyuan, Fang, Bingliang, Fang, Xuexun, Fang, Dexing, Litchfield, David W., Aldape, Kenneth, Lu, Zhimin
Format: Article
Language:English
Subjects:
alpha Catenin - chemistry
alpha Catenin - metabolism
Amino Acid Sequence
beta Catenin - genetics
beta Catenin - metabolism
Binding Sites
Casein Kinase II - metabolism
Enzyme Activation - drug effects
Epidermal Growth Factor - pharmacology
Extracellular Signal-Regulated MAP Kinases - metabolism
Glioblastoma - enzymology
Glioblastoma - pathology
Humans
HUMDISEASE
Molecular Sequence Data
Neoplasm Invasiveness
Phosphorylation - drug effects
Phosphoserine - metabolism
Protein Binding - drug effects
PROTEINS
Receptor, Epidermal Growth Factor - metabolism
SIGNALING
Transcriptional Activation - drug effects
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Summary: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.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2009.09.034