Aberrant β-Catenin Signaling in Tuberous Sclerosis

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.

Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms

“…In this study, we used phospho-specific antibodies in immunohistochemical (IHC) analyses to dissect the mTOR pathway. Previously, we have shown that TSC-related AMLs exhibit evidence of mTOR activation 22,23 . As an example, Figures 2A and 2B illustrate the use of phospho-specific antibodies in a case of renal AML from a TSC patient with known TSC2 mutation.…”

Advances in behavioral genetics: mouse models of autism

“…WNT2 has been identified as a candidate gene for autism susceptibility. 11,269 Studies in rat and mouse TSC2 mutants have provided evidence that alterations in WNT signaling may be implicated in disease pathology of tuberous sclerosis, 270,271 although relevance to symptoms of autism has not been addressed. The targeted disruption of another member of the WNT signaling pathway, Dishevelled-1 (Dvl1), leads to altered home cage behavior and social interaction deficits, 40,272 reduced dendritic branching 273 and changes in the formation of synapses.…”

The ups and downs of Wnt signaling in prevalent neurological disorders

“…TSC is an autosomal dominant disorder characterized by benign tumors or hamartomas growing in the brain and on other vital organs such as the kidneys, heart, eyes, lungs and skin, and which is caused by defects/mutations on two genes: TSC1 (hamartin in chromosome 9) and TSC2 (tuberin in chromosome 16) (reviewed by Wiznitzer (2004)). Remarkably, TSC1 and TSC2 form a functional complex with components of the b-catenin degradation machinery, including GSK3b and axin, which negatively regulate b-catenin stability (Mak et al, 2003) and its activation of Wnt target genes (Mak et al, 2005). Intriguingly, loss of function of either TSC1 or TSC2 trigger an enlargement of somas and dendritic spines and alter the properties of functional synapses in postmitotic hippocampal neurons (Tavazoie et al, 2005).…”