The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin.
beta-Catenin-mediated Wnt signaling is essential in embryonic development and in adult tissues. Recent studies have demonstrated that Axin not only plays an important inhibitory role in coordinating beta-catenin degradation, but is itself degraded by the low-density-lipoprotein receptor-related protein (LRP)5/6 Wnt co-receptor. Here, we demonstrate that the endocytic adaptor molecule Disabled-2 (Dab2), which we have previously demonstrated to act as an inhibitor of beta-catenin signaling, interacts with Axin and prevents its interaction with and degradation by the LRP5 co-receptor, thereby increasing its half-life and stabilization. Dab2 levels induced during retinoic acid-induced differentiation of F9, or during transforming growth factor-beta-induced epithelial-mesenchymal transdifferentiation of mouse mammary epithelial cells result in the stabilization of Axin and concomitant inhibition of beta-catenin signaling. Ectopic expression of Dab2 in F9 cells as well as in transformed cell lines results in increased Axin expression and attenuation of Wnt-mediated signaling. We conclude that Dab2 may play an important role in the maintenance of the differentiated state and restrain Wnt-mediated proliferation through its association with and modulation of Axin.
Jiang
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Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Prunier
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C
Howe
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PH
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000494:pharmacology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D060466:Axin Protein; D015153:Blotting, Western; D018236:Carcinoma, Embryonal / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism; D047468:Immunoprecipitation; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; D060466:Axin Protein; C495267:CTNNB1 protein, mouse; C478773:Dab2 protein, mouse; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051176:beta Catenin; D014212:Tretinoin