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Integration of the Beta-Catenin-Dependent Wnt Pathway with Integrin Signaling through the Adaptor Molecule Grb2

  • Author(s): Crampton, Steve P.
  • Wu, Beibei
  • Park, Edward J.
  • Kim, Jai-Hyun
  • Solomon, Candice
  • Waterman, Marian L.
  • Hughes, Christopher W.
  • et al.
Creative Commons Attribution 4.0 International Public License
Abstract

Background

The complexity of wnt signaling likely stems from two sources: multiple pathways emanating from frizzled receptors in response to wnt binding, and modulation of those pathways and target gene responsiveness by context-dependent signals downstream of growth factor and matrix receptors. Both rac1 and c-jun have recently been implicated in wnt signaling, however their upstream activators have not been identified.

Methodology/Principal Findings

Here we identify the adapter protein Grb2, which is itself an integrator of multiple signaling pathways, as a modifier of β-catenin-dependent wnt signaling. Grb2 synergizes with wnt3A, constitutively active (CA) LRP6, Dvl2 or CA-β-catenin to drive a LEF/TCF-responsive reporter, and dominant negative (DN) Grb2 or siRNA to Grb2 block wnt3A-mediated reporter activity. MMP9 is a target of β-catenin-dependent wnt signaling, and an MMP9 promoter reporter is also responsive to signals downstream of Grb2. Both a jnk inhibitor and DN-c-jun block transcriptional activation downstream of Dvl2 and Grb2, as does DN-rac1. Integrin ligation by collagen also synergizes with wnt signaling as does overexpression of Focal Adhesion Kinase (FAK), and this is blocked by DN-Grb2.

Conclusions/Significance

These data suggest that integrin ligation and FAK activation synergize with wnt signaling through a Grb2-rac-jnk-c-jun pathway, providing a context-dependent mechanism for modulation of wnt signaling.

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