Akt participation in the Wnt signaling pathway through Dishevelled

Area of Science:

• Molecular Biology
• Cell Signaling
• Biochemistry

Background:

• Glycogen synthase kinase 3beta (GSK3beta) inactivation and beta-catenin stabilization are crucial for Wnt target gene activation.
• The role of Akt in Wnt signaling remains largely uncharacterized, despite its known regulation of GSK3alpha/beta in the phosphatidylinositide 3-OH kinase pathway.

Purpose of the Study:

• To investigate the role of Akt in Wnt signaling.
• To elucidate the mechanism by which Akt influences beta-catenin levels and Wnt target gene activation.

Main Methods:

• Wnt or Dishevelled (Dvl) expression was used to modulate signaling.
• Akt activity was measured and its interaction with the Axin-GSK3beta complex was assessed.
• Phosphorylation of GSK3beta and levels of free beta-catenin were quantified.
• Dominant-negative Akt was employed in Wnt-overexpressing PC12 cells to assess its impact on differentiation.

Main Results:

• Wnt or Dvl expression led to increased Akt activity.
• Activated Akt, in conjunction with Dvl, bound to the Axin-GSK3beta complex.
• Akt phosphorylated GSK3beta, resulting in increased levels of free beta-catenin.
• In Wnt-overexpressing PC12 cells, dominant-negative Akt reduced free beta-catenin and nerve growth factor-induced differentiation.

Conclusions:

• Akt acts as a significant regulator of the Wnt signaling pathway.
• Akt functions in association with Dishevelled (Dvl) to modulate GSK3beta activity and beta-catenin stability.
• These findings highlight a novel mechanism linking Akt signaling to Wnt pathway activation and cellular differentiation.