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PMID:14966280

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Citation

Cong, F, Schweizer, L and Varmus, H (2004) Casein kinase Iepsilon modulates the signaling specificities of dishevelled. Mol. Cell. Biol. 24:2000-11

Abstract

Wnt signaling is critical to many aspects of development, and aberrant activation of the Wnt signaling pathway can cause cancer. Dishevelled (Dvl) protein plays a central role in this pathway by transducing the signal from the Wnt receptor complex to the beta-catenin destruction complex. Dvl also plays a pivotal role in the planar cell polarity pathway that involves the c-Jun N-terminal kinase (JNK). How functions of Dvl are regulated in these two distinct pathways is not clear. We show that deleting the C-terminal two-thirds of Dvl, which includes the PDZ and DEP domains and is essential for Dvl-induced JNK activation, rendered the molecule a much more potent activator of the beta-catenin pathway. We also found that casein kinase Iepsilon (CKIepsilon), a previously identified positive regulator of Wnt signaling, stimulated Dvl activity in the Wnt pathway, but dramatically inhibited Dvl activity in the JNK pathway. Consistent with this, overexpression of CKIepsilon in Drosophila melanogaster stimulated Wnt signaling and disrupted planar cell polarity. We also observed a correlation between the localization and the signaling activity of Dvl in the beta-catenin pathway and the JNK pathway. Furthermore, by using RNA interference, we demonstrate that the Drosophila CKIepsilon homologue Double time positively regulates the beta-catenin pathway through Dvl and negatively regulates the Dvl-induced JNK pathway. We suggest that CKIepsilon functions as a molecular switch to direct Dvl from the JNK pathway to the beta-catenin pathway, possibly by altering the conformation of the C terminus of Dvl.

Links

PubMed PMC350543

Keywords

Adaptor Proteins, Signal Transducing; Animals; Axin Protein; Casein Kinase Iepsilon; Casein Kinases; Cell Line; Cell Polarity; Cytoskeletal Proteins/metabolism; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila melanogaster/genetics; Drosophila melanogaster/physiology; Enzyme Activation; Humans; Isoenzymes/genetics; Isoenzymes/metabolism; JNK Mitogen-Activated Protein Kinases; Mice; Mitogen-Activated Protein Kinases/metabolism; Phosphoproteins/genetics; Phosphoproteins/metabolism; Protein Kinases/genetics; Protein Kinases/metabolism; Proto-Oncogene Proteins/metabolism; RNA Interference; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Repressor Proteins/genetics; Repressor Proteins/metabolism; Signal Transduction/physiology; Subcellular Fractions/metabolism; Trans-Activators/metabolism; Wing/cytology; Wing/metabolism; Wnt Proteins; Zebrafish Proteins; beta Catenin

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:DVL1

acts_upstream_of_or_within

GO:0060071: Wnt signaling pathway, planar cell polarity pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DVL1

acts_upstream_of_or_within

GO:0060071: Wnt signaling pathway, planar cell polarity pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1351660

P

Seeded From UniProt

complete

MOUSE:DVL1

involved_in

GO:0060070: canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DVL1

involved_in

GO:0060070: canonical Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1351660

P

Seeded From UniProt

complete

MOUSE:KC1E

acts_upstream_of_or_within

GO:0030178: negative regulation of Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:94941

P

Seeded From UniProt

complete

MOUSE:KC1E

acts_upstream_of_or_within

GO:0034613: cellular protein localization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:KC1E

acts_upstream_of_or_within

GO:0006468: protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_participant:(MGI:MGI:94941)

Seeded From UniProt

complete

MOUSE:KC1E

acts_upstream_of_or_within

GO:0090263: positive regulation of canonical Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:94941

P

Seeded From UniProt

complete


See also

References

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