EGF-induced ERK activation promotes CK2-mediated disassociation of alpha-Catenin from beta-Catenin and transactivation of beta-Catenin.
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 CK2alpha-dependent phosphorylation of alpha-catenin at S641. ERK2, which is activated by EGFR signaling, directly binds to CK2alpha via the ERK2 docking groove and phosphorylates CK2alpha primarily at T360/S362, subsequently enhancing CK2alpha 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 Wnt pathways in tumor development.
Ji
Haitao
H
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
Wang
Ji
J
Nika
Heinz
H
Hawke
David
D
Keezer
Susan
S
Ge
Qingyuan
Q
Fang
Bingliang
B
Fang
Xuexun
X
Fang
Dexing
D
Litchfield
David W
DW
Aldape
Kenneth
K
Lu
Zhimin
Z
D000595:Amino Acid Sequence; D001665:Binding Sites; D047390:Casein Kinase II / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D051178:alpha Catenin / Q000737:chemistry / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
D051178:alpha Catenin; D051176:beta Catenin; D010768:Phosphoserine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D047390:Casein Kinase II; D048049:Extracellular Signal-Regulated MAP Kinases