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WNT-1 and HGF regulate GSK3 beta activity and beta-catenin signaling in mammary epithelial cells

J Papkoff1, M Aikawa

  • 1Department of Molecular Oncology, Megabios Corporation, Burlingame, California 94010, USA.

Biochemical and Biophysical Research Communications
|July 2, 1998
PubMed

Insights

Wnt-1 signaling reduces GSK3 activity, increasing beta-catenin. This pathway, also activated by HGF/SF, promotes nuclear beta-catenin accumulation and gene expression changes, impacting mammary oncogenesis.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Cancer research

Background:

  • Wnt-1 is a secreted glycoprotein involved in nervous system development and mammary oncogenesis.
  • Overexpression of Wnt-1 is linked to cancer development.
  • GSK3 (Glycogen synthase kinase 3) plays a role in cellular regulation.

Purpose of the Study:

  • To investigate the effect of Wnt-1 signaling on GSK3 activity and beta-catenin levels in mammary cells.
  • To elucidate the signal transduction pathway activated by Wnt-1 and HGF/SF.
  • To understand the downstream effects on gene expression.

Main Methods:

  • Analysis of GSK3 activity in mouse mammary cells.
  • Quantification of uncomplexed beta-catenin populations.
  • Assessment of protein-protein interactions between GSK3 beta and beta-catenin.
  • Treatment with Wnt-1 and HGF/SF.
  • Monitoring of beta-catenin nuclear accumulation.
  • Assay of LEF/Tcf responsive reporter gene activity.

Main Results:

  • Wnt-1 transformation of mammary cells decreases GSK3 activity.
  • Wnt-1 signaling leads to a Wnt-1 dependent increase in uncomplexed beta-catenin.
  • Wnt-1 increases the association between GSK3 beta and beta-catenin without altering steady-state levels.
  • HGF/SF treatment similarly causes a transient decrease in GSK3 activity and an increase in uncomplexed beta-catenin.
  • Both Wnt-1 and HGF/SF induce nuclear accumulation of beta-catenin and activate LEF/Tcf responsive genes.

Conclusions:

  • A key signal transduction pathway activated by Wnt-1 and HGF/SF involves decreased GSK3 beta activity.
  • This pathway results in an increased free pool and nuclear accumulation of beta-catenin.
  • The pathway ultimately leads to alterations in gene expression, relevant to mammary oncogenesis.

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