1. Aberrant beta-catenin signaling in tuberous sclerosis.
- Author
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Mak BC, Kenerson HL, Aicher LD, Barnes EA, and Yeung RS
- Subjects
- Adaptor Proteins, Signal Transducing, Angiomyolipoma metabolism, Animals, Axin Protein, Connexin 43 metabolism, Cyclin D1 metabolism, Dishevelled Proteins, Glycogen Synthase Kinase 3 metabolism, Humans, Immunohistochemistry, Immunoprecipitation, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Lymphangioleiomyomatosis metabolism, Mice, Mutation, Missense, Phosphoproteins metabolism, Phosphorylation, Rats, Repressor Proteins genetics, Repressor Proteins metabolism, Tuberous Sclerosis pathology, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Wnt Proteins, beta Catenin, Cytoskeletal Proteins metabolism, Signal Transduction physiology, Trans-Activators metabolism, Tuberous Sclerosis metabolism
- Abstract
The pathology associated with tuberous sclerosis complex (TSC) shows diverse phenotypes that suggest abnormal signaling of multiple pathways. Besides the negative regulatory role of the TSC1/TSC2 proteins on mTOR, we have reported an effect on beta-catenin signaling at the level of the degradation complex in vitro. The TSC1/TSC2 complex associates with GSK3 and Axin and promotes beta-catenin degradation to inhibit Wnt-stimulated TCF/LEF-dependent transcription. Here, we show that beta-catenin and its effectors, cyclin D1 and connexin 43, were up-regulated in TSC-related angiomyolipomas and lymphangioleiomyomatosis. This was supported by the failure of three disease-causing TSC2 missense mutants to inhibit Wnt signaling. Further, the interaction between TSC1/TSC2 and components of the beta-catenin degradation complex was dependent on Wnt stimulation such that binding of tuberin to GSK3 and Axin was reduced in the presence of Wnt whereas the tuberin-Dishevelled interaction was increased. GSK3 activity played a role in regulating the assembly/stability of the degradation complex. Inhibition of GSK3 by lithium chloride reduced its association with TSC1 whereas disruption of GSK3-phosphorylation sites in TSC1 reduced interaction between TSC2 and TSC1. Collectively, our data provide further evidence that beta-catenin signaling plays a role in TSC pathogenesis in vivo and suggest a novel role of GSK3 in modulating the TSC1/TSC2 complex through TSC1 phosphorylation.
- Published
- 2005
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