Re-evaluating the role of Frat in Wnt-signal transduction.
Frat proteins are potent activators of canonical Wnt-signal transduction. By binding to GSK3, Frat prevents the phosphorylation and concomitant degradation of beta-catenin and allows the activation of downstream target genes by beta-catenin/TCF complexes. The identification of the Xenopus Frat homologue GBP as an essential component of the maternal Wnt-pathway during embryonic axis formation suggested that Frat might fulfill a similar role in higher vertebrates. As a result most, if not all, studies addressing Frat function have focused on its ability to bind GSK3 and induce signaling through beta-catenin/TCF. Consequently, Frat has been advocated as the "missing link" that bridged signaling from Dishevelled to GSK3 in the canonical Wnt-pathway. Recent mouse-knockout studies however, call for a reevaluation of the physiological role of Frat. Mice that lack all Frat-family members appear to be normal and display no obvious defects in beta-catenin/TCF signaling. This observation reopens the question as to how GSK3 activity is controlled in vertebrate canonical Wnt-signal transduction in view of the apparent dispensability of Frat. Here we will review the studies that have been conducted on Frat proteins to date, with a specific focus on those that implicate a role for Frat in Wnt-signal transduction. In addition, we will discuss potential alternatives for the endogenous function of Frat.
van Amerongen
Renée
R
Netherlands Cancer Institute, Division of Molecular Genetics and Centre of Biomedical Genetics, Amsterdam, The Netherlands.
Berns
Anton
A
D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D020816:Amino Acid Motifs; D000818:Animals; D017173:Caenorhabditis elegans; D045744:Cell Line, Tumor; D004330:Drosophila; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010766:Phosphorylation; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D014981:Xenopus; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C491819:FRAT1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D008156:Luciferases; D038362:Glycogen Synthase Kinase 3