EGF-induced ERK activation promotes CK2-mediated disassociation of alpha-Catenin from beta-Catenin and transactivation of beta-Catenin

Mol Cell. 2009 Nov 25;36(4):547-59. doi: 10.1016/j.molcel.2009.09.034.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Casein Kinase II / metabolism*
  • Enzyme Activation / drug effects
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Glioblastoma / enzymology
  • Glioblastoma / pathology
  • Humans
  • Molecular Sequence Data
  • Neoplasm Invasiveness
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Protein Binding / drug effects
  • Transcriptional Activation / drug effects*
  • alpha Catenin / chemistry
  • alpha Catenin / metabolism*
  • beta Catenin / genetics*
  • beta Catenin / metabolism

Substances

  • alpha Catenin
  • beta Catenin
  • Phosphoserine
  • Epidermal Growth Factor
  • ErbB Receptors
  • Casein Kinase II
  • Extracellular Signal-Regulated MAP Kinases