Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation.
Dapper was isolated in a screen for proteins interacting with Dishevelled, a key factor in Wnt signaling. Dapper and Dishevelled colocalize intracellularly and form a complex with Axin, GSK-3, CKI, and beta-catenin. Overexpression of Dapper increases Axin and GSK-3 in this complex, resulting in decreased soluble beta-catenin and decreased activation of beta-catenin-responsive genes. Dapper also inhibits activation by Dishevelled of c-Jun N-terminal kinase (JNK), a component of beta-catenin-independent Frizzled signaling. Inhibition of Dapper activates both beta-catenin-responsive genes and an AP1-responsive promoter, demonstrating that Dapper is a general Dishevelled antagonist. Depletion of maternal Dapper RNA from Xenopus embryos results in loss of notochord and head structures, demonstrating that Dapper is required for normal vertebrate development.
Cheyette
Benjamin N R
BN
Howard Hughes Medical Institute, Department of Pharmacology and Center for Developmental Biology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Waxman
Joshua S
JS
Miller
Jeffrey R
JR
Takemaru
Ken-Ichi
K
Sheldahl
Laird C
LC
Khlebtsova
Natasha
N
Fox
Eric P
EP
Earnest
Thomas
T
Moon
Randall T
RT
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D060466:Axin Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D047388:Casein Kinases; D017124:Conserved Sequence; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072261:Dishevelled Proteins; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3; D006367:HeLa Cells; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009672:Notochord / Q000196:embryology* / Q000378:metabolism; D009687:Nuclear Proteins; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators; D014714:Vertebrates; D051153:Wnt Proteins; D029867:Xenopus Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014982:Xenopus laevis; D029961:Zebrafish Proteins; D051176:beta Catenin
D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C454443:DACT1 protein, Xenopus; C491683:DACT1 protein, human; C514734:Dact2 protein, mouse; D000072261:Dishevelled Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C555454:axin1 protein, Xenopus; D051176:beta Catenin; D011494:Protein Kinases; D047388:Casein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases