Vertebrate proteins related to Drosophila Naked Cuticle bind Dishevelled and antagonize Wnt signaling.
Wnt signals control cell fate decisions and orchestrate cell behavior in metazoan animals. In the fruit fly Drosophila, embryos defective in signaling mediated by the Wnt protein Wingless (Wg) exhibit severe segmentation defects. The Drosophila segment polarity gene naked cuticle (nkd) encodes an EF hand protein that regulates early Wg activity by acting as an inducible antagonist. Nkd antagonizes Wg via a direct interaction with the Wnt signaling component Dishevelled (Dsh). Here we describe two mouse and human proteins, Nkd1 and Nkd2, related to fly Nkd. The most conserved region among the fly and vertebrate proteins, the EFX domain, includes the putative EF hand and flanking sequences. EFX corresponds to a minimal domain required for fly or vertebrate Nkd to interact with the basic/PDZ domains of fly Dsh or vertebrate Dvl proteins in the yeast two-hybrid assay. During mouse development, nkd1 and nkd2 are expressed in multiple tissues in partially overlapping, gradient-like patterns, some of which correlate with known patterns of Wnt activity. Mouse Nkd1 can block Wnt1-mediated, but not beta-catenin-mediated, activation of a Wnt-dependent reporter construct in mammalian cell culture. Misexpression of mouse nkd1 in Drosophila antagonizes Wg function. The data suggest that the vertebrate Nkd-related proteins, similar to their fly counterpart, may act as inducible antagonists of Wnt signals.
Wharton
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KA
Department of Developmental Biology, Howard Hughes Medical Institute, Beckman Center, B300, Stanford School of Medicine, 279 Campus Drive, Stanford, California 94305, USA. keith.wharton@utsouthwestern.edu
Zimmermann
G
G
Rousset
R
R
Scott
M P
MP
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D000072261:Dishevelled Proteins; D004330:Drosophila / Q000254:growth & development; D029721:Drosophila Proteins; D020832:EF Hand Motifs; D006801:Humans; D017403:In Situ Hybridization; D019476:Insect Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009024:Morphogenesis; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013045:Species Specificity; D014018:Tissue Distribution; D020798:Two-Hybrid System Techniques; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins
D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D019476:Insect Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins; C000606588:dsh protein, Drosophila; C405336:nkd protein, Drosophila