The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling.
Wnt signals control decisive steps in development and can induce the formation of tumors. Canonical Wnt signals control the formation of the embryonic axis, and are mediated by stabilization and interaction of beta-catenin with Lef/Tcf transcription factors. An alternative branch of the Wnt pathway uses JNK to establish planar cell polarity in Drosophila and gastrulation movements in vertebrates. We describe here the vertebrate protein Diversin that interacts with two components of the canonical Wnt pathway, Casein kinase Iepsilon (CKIepsilon) and Axin/Conductin. Diversin recruits CKIepsilon to the beta-catenin degradation complex that consists of Axin/Conductin and GSK3beta and allows efficient phosphorylation of beta-catenin, thereby inhibiting beta-catenin/Tcf signals. Morpholino-based gene ablation in zebrafish shows that Diversin is crucial for axis formation, which depends on beta-catenin signaling. Diversin is also involved in JNK activation and gastrulation movements in zebrafish. Diversin is distantly related to Diego of Drosophila, which functions only in the pathway that controls planar cell polarity. Our data show that Diversin is an essential component of the Wnt-signaling pathway and acts as a molecular switch, which suppresses Wnt signals mediated by the canonical beta-catenin pathway and stimulates signaling via JNK.
Max Delbrueck-Center for Molecular Medicine, D-13092 Berlin, Germany.
Thomas
T
Schwarz-Romond
Christian
C
Asbrand
Jeroen
J
Bakkers
Michael
M
Kühl
Hans-Joerg
HJ
Schaeffer
Jörg
J
Huelsken
Jürgen
J
Behrens
Matthias
M
Hammerschmidt
Walter
W
Birchmeier
D000818:Animals; D017487:Ankyrins / Q000737:chemistry; D060466:Axin Protein; D015153:Blotting, Western; D047388:Casein Kinases; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000737:chemistry* / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004330:Drosophila; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D051153:Wnt Proteins; D014981:Xenopus; D029867:Xenopus Proteins / Q000096:biosynthesis / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000737:chemistry; D051176:beta Catenin
C464904:ANKRD6 protein, Xenopus; C464902:ANKRD6 protein, human; C491761:AXIN2 protein, human; C464903:Ankrd6 protein, mouse; D017487:Ankyrins; D060466:Axin Protein; C111729:Axin2 protein, mouse; C495266:CTNNB1 protein, Xenopus; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C464905:ankrd6b protein, zebrafish; D051176:beta Catenin; C495269:ctnnb1 protein, zebrafish; C094522:wnt8b protein, zebrafish; D011494:Protein Kinases; D047388:Casein Kinases