Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling

Frizzled related proteins (FRPs) comprise a family of secreted molecules th at contain an N-terminal cysteine-rich domain (CRD) highly similar to the C RDs of the frizzled family of membrane-anchored Wnt receptors. FRPs have be en shown to interact with Wnt proteins and antagonize Wnt signaling in a Xe nopus developmental model. Fire demonstrated that FRP antagonizes the Wnt-i nduced increase in uncomplexed beta-catenin in both transient cotransfectio n and stable transformation models, where Wnt-induced morphological alterat ions are inhibited as well. We showed further that FRP inhibits Wnt signali ng in a paracrine mode using a T-cell factor luciferase reporter to measure Wnt function. Investigation of the mechanisms responsible for FRP inhibiti on revealed that FRP forms complexes with WNT-1 or WNT-2 through its CRD do main. Transfection analysis with FRPs containing different tags revealed th at FRP itself forms complexes and that this ability is conferred by its CRD domain. Finally, we demonstrated by cotransfection that FRP forms complexe s with a prototype frizzled. AU of these findings are consistent with a mod el by which FRP inhibits Wnt signaling through interactions with Wnt and/or formation of nonfunctional complexes with the frizzled receptor.