Purification and molecular cloning of a secreted, frizzled-related WNT antagonist
Frizzled polypeptides are integral membrane proteins that recently were shown to function as receptors for Wnt signaling molecules. Here, we report the identification of a novel, heparin-binding, 36 kDa Frizzled-related protein (FRP) that was purified from the conditioned medium of a human embryonic lung fibroblast line. Degenerate oligonucleotides, based on the amino-terminal sequence of the purified protein, were used to isolate corresponding cDNA clones. These encoded a 313-amino acid polypeptide, containing a cysteine-rich domain of ∼110 residues that was 30-40% identical to the putative ligand-binding domain of Frizzled proteins. A 4.4 kb transcript of the FRP gene is present in many organs, and homologs of the gene are detectable in DNA from several vertebrate species. In biosynthetic studies, FRP was secreted but, like Wnts, tended to remain associated with cells. When co-expressed with several Wnt family members in earlyXenopus embryos, FRP antagonized Wnt-dependent duplication of the embryonic dorsal axis. These results indicate that FRP may function as an inhibitor of Wnt action during development and in the adult.
Rubin, J; He, X; Kelley, M; Uren, A; Schaudies, P; Popescu, N; Rudikoff, S; Aaronson, S; Varmus, H; Finch, P
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