The Axin-like protein PRY-1 is a negative regulator of a canonical Wnt pathway in C. elegans.
Axin, APC, and the kinase GSK3 beta are part of a destruction complex that regulates the stability of the Wnt pathway effector beta-catenin. In C. elegans, several Wnt-controlled developmental processes have been described, but an Axin ortholog has not been found in the genome sequence and SGG-1/GSK3 beta, and the APC-related protein APR-1 have been shown to act in a positive, rather than negative fashion in Wnt signaling. We have shown previously that the EGL-20/Wnt-dependent expression of the homeobox gene mab-5 in the Q neuroblast lineage requires BAR-1/beta-catenin and POP-1/Tcf. Here, we have investigated how BAR-1 is regulated by the EGL-20 pathway. First, we have characterized a negative regulator of the EGL-20 pathway, pry-1. We show that pry-1 encodes an RGS and DIX domain-containing protein that is distantly related to Axin/Conductin. Our results demonstrate that despite its sequence divergence, PRY-1 is a functional Axin homolog. We show that PRY-1 interacts with BAR-1, SGG-1, and APR-1 and that overexpression of PRY-1 inhibits mab-5 expression. Furthermore, pry-1 rescues the zebrafish axin1 mutation masterblind, showing that it can functionally interact with vertebrate destruction complex components. Finally, we show that SGG-1, in addition to its positive regulatory role in early embryonic Wnt signaling, may function as a negative regulator of the EGL-20 pathway. We conclude that a highly divergent destruction complex consisting of PRY-1, SGG-1, and APR-1 regulates BAR-1/beta-catenin signaling in C. elegans.
Korswagen
Hendrik C
HC
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, 3584 CT Utrecht, The Netherlands. rkors@niob.knaw.nl
Coudreuse
Damien Y M
DY
Betist
Marco C
MC
van de Water
Sandra
S
Zivkovic
Danica
D
Clevers
Hans C
HC
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D015801:Helminth Proteins / Q000502:physiology*; D006609:High Mobility Group Proteins / Q000378:metabolism; D006358:Hot Temperature; D019476:Insect Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008164:Luminescent Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012097:Repressor Proteins; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D013489:Suppression, Genetic; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C555451:AXIN1 protein, human; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C117259:Egl-20 protein, C elegans; D006023:Glycoproteins; D015801:Helminth Proteins; D006609:High Mobility Group Proteins; D019476:Insect Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; C117260:Pry-1 protein, C elegans; D012097:Repressor Proteins; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C115014:bar-1 protein, C elegans; D051176:beta Catenin; C096787:pop-1 protein, C elegans; C094522:wnt8b protein, zebrafish; C067715:APR-1 pheromone-binding protein, Antheraea pernyi; D049452:Green Fluorescent Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3