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Abstract
Frat proteins are potent activators of canonical Wnt-signal transduction. By binding to GSK3,Frat prevents the phosphorylation and concomitant degradation of ?-catenin and allows theactivation of downstream target genes by ?-catenin/TCF complexes. The identification of theXenopus Frat homologue GBP as an essential component of the maternal Wnt-pathway duringembryonic 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 bindGSK3 and induce signaling through ?-catenin/TCF. Consequently, Frat has been advocated asthe “missing link” that bridged signaling from Dishevelled to GSK3 in the canonicalWnt-pathway. Recent mouse-knockout studies however, call for a re-evaluation of thephysiological role of Frat. Mice that lack all Frat-family members appear to be normal anddisplay no obvious defects in ?-catenin/TCF signaling. This observation re-opens the questionas to how GSK3 activity is controlled in vertebrate canonical Wnt-signal transduction in viewof the apparent dispensability of Frat. Here we will review the studies that have beenconducted on Frat proteins to date, with a specific focus on those that implicate a role for Fratin Wnt-signal transduction. In addition, we will discuss potential alternatives for theendogenous function of Frat.