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Re-evaluating the role of Frat in Wnt-signal transduction

Renée van Amerongen1, Anton Berns

  • 1Netherlands Cancer Institute, Division of Molecular Genetics and Centre of Biomedical Genetics, Amsterdam, The Netherlands.

Cell Cycle (Georgetown, Tex.)
|August 6, 2005
PubMed

Insights

Frat proteins, once thought essential for Wnt signaling by inhibiting GSK3, may not be physiologically indispensable. Mouse knockout studies reveal no obvious defects, questioning Frat's role in beta-catenin/TCF pathway regulation.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Cell Signaling

Background:

  • Frat proteins activate canonical Wnt signaling by inhibiting Glycogen Synthase Kinase 3 (GSK3).
  • This inhibition prevents beta-catenin degradation, enabling downstream gene activation via beta-catenin/TCF complexes.
  • The Xenopus homologue GBP's role in axis formation suggested conserved Frat function in vertebrates.

Purpose of the Study:

  • To review existing literature on Frat protein function in Wnt signal transduction.
  • To reevaluate the physiological role of Frat in light of recent knockout studies.
  • To discuss alternative mechanisms for GSK3 regulation in the Wnt pathway.

Main Methods:

  • Literature review of studies on Frat proteins and Wnt signaling.
  • Analysis of mouse knockout studies investigating Frat-family member functions.
  • Discussion of potential alternative pathways for Wnt signal transduction.

Main Results:

  • Most studies focused on Frat's interaction with GSK3 and its role in beta-catenin/TCF signaling.
  • Mouse knockout studies show that the absence of all Frat-family members results in normal development without apparent Wnt pathway defects.
  • This suggests Frat may not be essential for canonical Wnt signaling in vertebrates.

Conclusions:

  • The physiological role of Frat proteins in vertebrate Wnt signal transduction requires reevaluation.
  • Frat's presumed essential function as a bridge between Dishevelled and GSK3 is challenged by knockout data.
  • Alternative mechanisms likely control GSK3 activity in the canonical Wnt pathway.

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