Casein kinase Iε modulates the signaling specificities of dishevelled Journal Article
| Authors: | Cong, F.; Schweizer, L.; Varmus, H. |
| Article Title: | Casein kinase Iε modulates the signaling specificities of dishevelled |
| 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 β-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 β-catenin pathway. We also found that casein kinase Iε (CKIε), 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 CKIε 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 β-catenin pathway and the JNK pathway. Furthermore, by using RNA interference, we demonstrate that the Drosophila CKIε homologue Double time positively regulates the β-catenin pathway through Dvl and negatively regulates the Dvl-induced JNK pathway. We suggest that CKIε functions as a molecular switch to direct Dvl from the JNK pathway to the β-catenin pathway, possibly by altering the conformation of the C terminus of Dvl. |
| Keywords: | signal transduction; mitogen activated protein kinase; adolescent; controlled study; unclassified drug; oncoprotein; human cell; genetics; proto-oncogene proteins; nonhuman; protein conformation; protein domain; protein function; protein localization; animal cell; mouse; animal; cytology; metabolism; animals; mice; animal tissue; gene overexpression; protein kinases; stress activated protein kinase; carboxy terminal sequence; cell line; protein; rna interference; enzyme activation; physiology; animalia; regulatory mechanism; hybrid protein; recombinant fusion proteins; nucleotide sequence; transactivator protein; adaptor proteins, signal transducing; phosphoproteins; cell polarity; cell fractionation; development; trans-activators; drosophila melanogaster; wnt proteins; mitogen-activated protein kinases; beta catenin; repressor protein; repressor proteins; wnt protein; drosophila proteins; protein kinase; signal transducing adaptor protein; ctnnb1 protein, human; subcellular fractions; phosphoprotein; isoenzymes; protein modification; cytoskeleton protein; drosophila protein; cytoskeletal proteins; frizzled protein; forelimb; jnk mitogen-activated protein kinases; wing; isoenzyme; dishevelled protein; pdz protein; melanogaster; casein kinase i; zebrafish proteins; dishevelled proteins; zebrafish protein; casein kinase iepsilon; cancer; humans; human; priority journal; article; casein kinases; dep protein; double time protein; axin protein; casein kinase; catnb protein, mouse; dco protein, drosophila; molecular switch |
| Journal Title: | Molecular and Cellular Biology |
| Volume: | 24 |
| Issue: | 5 |
| ISSN: | 0270-7306 |
| Publisher: | American Society for Microbiology |
| Date Published: | 2004-03-01 |
| Start Page: | 2000 |
| End Page: | 2011 |
| Language: | English |
| DOI: | 10.1128/mcb.24.5.2000-2011.2004 |
| PROVIDER: | scopus |
| PMCID: | PMC350543 |
| PUBMED: | 14966280 |
| DOI/URL: | |
| Notes: | Mol. Cell. Biol. -- Cited By (since 1996):90 -- Export Date: 16 June 2014 -- CODEN: MCEBD -- Molecular Sequence Numbers: GENBANK: AF055583, L26974, M23233, U55848; -- Source: Scopus |
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