Matrix rigidity activates Wnt signaling through down-regulation of Dickkopf-1 protein

J Biol Chem. 2013 Jan 4;288(1):141-51. doi: 10.1074/jbc.M112.431411. Epub 2012 Nov 14.


Cells respond to changes in the physical properties of the extracellular matrix with altered behavior and gene expression, highlighting the important role of the microenvironment in the regulation of cell function. In the current study, culture of epithelial ovarian cancer cells on three-dimensional collagen I gels led to a dramatic down-regulation of the Wnt signaling inhibitor dickkopf-1 with a concomitant increase in nuclear β-catenin and enhanced β-catenin/Tcf/Lef transcriptional activity. Increased three-dimensional collagen gel invasion was accompanied by transcriptional up-regulation of the membrane-tethered collagenase membrane type 1 matrix metalloproteinase, and an inverse relationship between dickkopf-1 and membrane type 1 matrix metalloproteinase was observed in human epithelial ovarian cancer specimens. Similar results were obtained in other tissue-invasive cells such as vascular endothelial cells, suggesting a novel mechanism for functional coupling of matrix adhesion with Wnt signaling.

Publication types

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

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Line, Tumor
  • Collagen / metabolism
  • Down-Regulation*
  • Extracellular Matrix / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Microscopy, Electron, Scanning / methods
  • Mutation
  • Neoplasm Metastasis
  • Rats
  • Signal Transduction
  • Subcellular Fractions / metabolism
  • Wnt Proteins / metabolism


  • DKK1 protein, human
  • Dkk1 protein, mouse
  • Dkk1 protein, rat
  • Intercellular Signaling Peptides and Proteins
  • Wnt Proteins
  • Collagen
  • Matrix Metalloproteinases