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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Angiomyolipoma / metabolism
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Animals
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Axin Protein
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Connexin 43 / metabolism
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Cyclin D1 / metabolism
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Cytoskeletal Proteins / metabolism*
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Dishevelled Proteins
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Glycogen Synthase Kinase 3 / metabolism
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Humans
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Immunohistochemistry
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Immunoprecipitation
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Lymphangioleiomyomatosis / metabolism
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Mice
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Mutation, Missense
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Phosphoproteins / metabolism
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Phosphorylation
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Rats
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Signal Transduction / physiology*
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Trans-Activators / metabolism*
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Tuberous Sclerosis / metabolism*
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Tuberous Sclerosis / pathology
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Wnt Proteins
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beta Catenin
Substances
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Adaptor Proteins, Signal Transducing
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Axin Protein
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Connexin 43
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Ctnnb1 protein, rat
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Cytoskeletal Proteins
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Dishevelled Proteins
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Intercellular Signaling Peptides and Proteins
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Phosphoproteins
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Repressor Proteins
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TSC1 protein, human
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TSC2 protein, human
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Trans-Activators
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Tsc1 protein, mouse
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Tsc1 protein, rat
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Tsc2 protein, mouse
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Tsc2 protein, rat
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Wnt Proteins
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beta Catenin
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Cyclin D1
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Glycogen Synthase Kinase 3