Feedback in the β-catenin destruction complex imparts bistability and cellular memory

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Wnt ligands are classical morphogens where cellular response strength correlates with ligand concentration.
• The Wnt pathway regulates crucial cellular processes, including development and disease.

Purpose of the Study:

• To investigate the emergent property of bistability in Wnt signaling.
• To elucidate the role of feedback mechanisms within the Wnt destruction complex.
• To understand how cellular responses and memory are established upon Wnt pathway stimulation.

Main Methods:

• Biochemical reconstitution of Wnt destruction complex proteins.
• Identification of positive feedback loops between Axin and glycogen synthase kinase 3 (GSK3).
• Theoretical modeling and experimental validation using cellular β-catenin concentration measurements.

Main Results:

• A positive feedback loop between Axin and GSK3 was identified within the Wnt destruction complex.
• Theoretical modeling predicted bistable behavior of the destruction complex.
• Experimental data confirmed an
• all-or-none
• cellular response with hysteresis (memory) in cytoplasmic β-catenin levels.
• Inhibition of GSK3 abolished bistability and memory, converting the response to a graded one.

Conclusions:

• The Wnt destruction complex exhibits emergent bistability driven by positive feedback between Axin and GSK3.
• This bistability provides a mechanism for switch-like cellular responses and sustained memory of Wnt pathway stimulation.
• Understanding this mechanism is key to deciphering Wnt pathway regulation in development and disease.