Inhibition of the Wnt/beta-catenin pathway by the WWOX tumor suppressor protein.
The WWOX gene encodes a candidate tumor suppressor protein (WWOX) implicated in a variety of human diseases such as cancer. To better understand the molecular mechanisms of WWOX action, we investigated novel partners of this protein. Using the two-hybrid system and a coimmunoprecipitation assay, we observed a physical association between WWOX and the Dishevelled protein (Dvl) family signaling elements involved in the Wnt/beta-catenin pathway. We found that enforced WWOX expression inhibited, and inhibition of endogenous WWOX expression stimulated the transcriptional activity of the Wnt/beta-catenin pathway. Inhibition of endogenous WWOX expression also enhanced the effect of Wnt-3a on beta-catenin stability. Moreover, we observed the sequestration of Dvl-2 wild type and Dvl-2NESm, a mutated form of Dvl-2 predominantly localized in the nucleus, in the cytoplasm compartment by WWOX. Our results indicate that WWOX is a novel inhibitor of the Wnt/beta-catenin pathway. WWOX would act, at least in part, by preventing the nuclear import of the Dvl proteins.
Bouteille
N
N
Centre René Huguenin, FNCLCC, St-Cloud, France.
Driouch
K
K
Hage
P El
PE
Sin
S
S
Formstecher
E
E
Camonis
J
J
Lidereau
R
R
Lallemand
F
F
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002451:Cell Compartmentation; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D000072261:Dishevelled Proteins; D016147:Genes, Tumor Suppressor; D006801:Humans; D047468:Immunoprecipitation; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010088:Oxidoreductases / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D000074584:WW Domain-Containing Oxidoreductase; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010750:Phosphoproteins; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human