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

• Published in: Journal of cell science Vol. 112 ( Pt 21); no. 21; pp. 3815 - 3820
• Main Authors: Dennis, S, Aikawa, M, Szeto, W, d'Amore, P A, Papkoff, J
• Format: Journal Article
• Language: English
• Published: England 01.11.1999
• Subjects: beta Catenin; Blotting, Western; Cell Line; Cytoskeletal Proteins - metabolism; Gene Expression Regulation, Developmental; Intercellular Signaling Peptides and Proteins; Membrane Proteins; Precipitin Tests; Proteins - metabolism; Proto-Oncogene Proteins - metabolism; Signal Transduction - physiology; Trans-Activators; Wnt Proteins; Wnt-5a Protein; Wnt1 Protein; Zebrafish Proteins
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.112.21.3815

The Wnt gene family encodes proteins that serve key roles in differentiation and development. Wnt proteins interact with seven transmembrane receptors of the Frizzled family and activate a signaling pathway leading to the nucleus. A primary biochemical effect of Wnt-1 signaling is the stabilization of cytoplasmic (beta)-catenin which, in association with transcription factors of the Lef/tcf family, regulates gene expression. The recent identification of a new class of secreted proteins with similarity to the extracellular, ligand-binding domain of Frizzled proteins, soluble Frizzled related proteins (sFRP), suggested that additional mechanisms could regulate Wnt signaling. Here we demonstrate that FrzA, a sFRP that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to Wnt-1 protein, but not Wnt-5a protein, and modulates Wnt-1 signaling. FrzA associated 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 Wnt-1 mediated increase in cytoplasmic (beta)-catenin levels as well as the Wnt-1 induction of transcription from a Lef/tcf reporter gene. The effects of FrzA on (beta)-catenin levels could be demonstrated when co-expressed with Wnt-1 or when individual cells expressing FrzA and Wnt-1 were co-cultured. These data demonstrate the existence of a negative regulatory mechanism mediated by the selective binding of FrzA to Wnt-1 protein.