A secreted Frizzled related protein, FrzA, selectively associates with Wnt-1 protein and regulates Wnt-1 signaling

The Wnt gene family encodes proteins that serve key roles in differentiatio n and development. Wnt proteins interact with seven transmembrane receptors of the Frizzled family and activate a signaling pathway leading to the nuc leus. A primary biochemical effect of Wnt-1 signaling is the stabilization of cytoplasmic beta-catenin which, in association with transcription factor s of the Lef/tcf family, regulates gene expression. The recent identificati on of a new class of secreted proteins with similarity to the extracellular , ligand-binding domain of Frizzled proteins, soluble Frizzled related prot eins (sFRP), suggested that additional mechanisms could regulate Wnt signal ing. Here we demonstrate that FrzA, a sFRP that is highly expressed in vasc ular endothelium and a variety of epithelium, specifically binds to Wnt-1 p rotein, but not Wnt-5a protein, and modulates Wnt-1 signaling. FrzA associa ted with Wnt-1 either when expressed in the same cell or when soluble FrzA was incubated with Wnt-1-expressing cells. FrzA efficiently inhibited the W nt-1 mediated increase in cytoplasmic beta-catenin levels as well as the Wn t-1 induction of transcription from a Lef/tcf reporter gene. The effects of FrzA on beta-catenin levels could be demonstrated when coexpressed with Wn t-1 or when individual cells expressing FrzA and Wnt-1 were co-cultured, Th ese data demonstrate the existence of a negative regulatory mechanism media ted by the selective binding of FrzA to Wnt-1 protein.