The Tuberin-Hamartin Complex Negatively Regulates β-Catenin Signaling Activity

Mak, Baldwin; Takemaru, Ken Ichi; Kenerson, Heidi L.; Moon, Randall T.; Yeung, Raymond S.

doi:10.1074/jbc.c200473200

Cited by 96 publications

(88 citation statements)

References 26 publications

(22 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the complex, by its binding to the small GTPase Rheb, inhibits mTORC1, it promotes mTORC2 signaling (Huang et al, 2008;Huang and Manning, 2009;Laplante and Sabatini, 2009). In addition, the TSC1-TSC2 complex can have an impact on cell proliferation through its positive control of the turnover of b-catenin (Mak et al, 2003;Jozwiak and Wlodarski, 2006;Barnes et al, 2010). We thus investigated the expression of the TSC complex and b-catenin in wtPC12 and PC12-27 cells.…”

Section: Resultsmentioning

confidence: 99%

A signaling loop of REST, TSC2 and β-catenin governs proliferation and function of PC12 neural cells

Tomasoni

Negrini

Fiordaliso

et al. 2011

Journal of Cell Science

View full text Add to dashboard Cite

SummaryThe RE-1-specific silencing transcription factor (REST or NRSF) is a transcription repressor that orchestrates differentiation and also operates in differentiated neurons and neurosecretory cells (neural cells). Its role in proliferation has been investigated so far only in rapidly growing tumors, with conflicting results: suppression in non-neural tumors, stimulation in medulloblastomas. Working with two clones of chromaffin-neuronal PC12 cells, which express different levels of REST, and using genetic complementation and knockdown approaches, we show that REST also promotes proliferation in differentiated neural cells. Mechanistically, this occurs by a signaling pathway involving REST, the GTPase-activating protein tuberin (TSC2) and the transcription co-factor b-catenin. In PC12 cells, raised expression of REST correlates with reduced TSC2 levels, nuclear accumulation and co-transcriptional activation of b-catenin, and increased expression of its target oncogenes Myc and Ccnd1, which might account for the proliferation advantage and the distinct morphology. Rest transcription is also increased, unveiling the existence of a self-sustaining, feed-forward REST-TSC2-b-catenin signaling loop that is also operative in another neural cell model, NT2/D1 cells. Transfection of REST, knockdown of TSC2 or forced expression of active b-catenin recapitulated the biochemical, functional and morphological properties of the high-expressing REST clone in wild-type PC12 cells. Upregulation of REST promoted proliferation and phenotypic changes, thus hindering neurosecretion. The new REST-TSC2-b-catenin signaling paradigm might have an important role in various aspects of neural cell physiology and pathology, including the regulation of proliferation and neurosecretion.

show abstract

Section: Resultsmentioning

confidence: 99%

A signaling loop of REST, TSC2 and β-catenin governs proliferation and function of PC12 neural cells

Tomasoni

Negrini

Fiordaliso

et al. 2011

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…FSCN1 has been shown to be up-regulated in a number of human cancers and functions to promote cancer cell migration and invasion (18). Interestingly, FSCN1 has been identified as a transcriptional target of ␤-catenin/T cell factor (TCF) signaling (19), and this signaling can be inhibited by the TSC1/TSC2 complex (7). Whether TSC1/TSC2 regulates FSCN1 via ␤-catenin/TCF signaling awaits further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…TSC1/TSC2-mTORC1 signaling activities and its capacity to regulate cell growth and macromolecular synthesis involves its ability to control mRNA translation, ribosome synthesis, metabolism-related gene expression, and autophagy (4). TSC1/TSC2 signaling can also impact the regulation of cell proliferation and cell adhesion/migration via interaction with many other signaling pathways, including B-Raf, ␤-catenin, ERM proteins, small GTPase Rho, and mTORC2-Akt signaling (5)(6)(7)(8). mTORC1 pharmacological inhibition and mutagenesis approaches have indicated that some of these functions are mTORC1-independent (6,8).…”

mentioning

confidence: 99%

mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization

Gan¹,

Sahin²,

Jiang³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

185

172

View full text Add to dashboard Cite

The Tuberous Sclerosis Complex component, TSC1, functions as a tumor suppressor via its regulation of diverse cellular processes, particularly cell growth. TSC1 exists in a complex with TSC2 and functions primarily as a key negative regulator of mammalian target of rapamycin complex 1 (mTORC1) signaling and protein synthesis, although the TSC1/TSC2 complex also shows mTORC1-independent outputs to other pathways. Here, we explored the role of TSC1 in various aspects of stem cell biology and dissected the extent to which TSC1 functions are executed via mTORC1-dependent versus mTORC1-independent pathways. Using hematopoietic stem cells (HSCs) as a model system, we demonstrate that somatic deletion of TSC1 produces striking stem cell and derivative effector cell phenotypes characterized by increased HSC cell cycling, mobilization, marked progressive depletion, defective longterm repopulating potential, and hematopoietic lineage developmental aberrations. On the mechanistic level, we further establish that TSC1 regulation of HSC quiescence and long-term repopulating potential and hematopoietic lineage development is mediated through mTORC1 signaling. In contrast, TSC1 regulation of HSC mobilization is effected in an mTORC1-independent manner, and gene profiling and functional analyses reveals the actin-bundling protein FSCN1 as a key TSC1/TSC2 target in the regulation of HSC mobilization. Thus, TSC1 is a critical regulator of HSC self-renewal, mobilization, and multilineage development and executes these actions via both mTORC1-dependent and -independent pathways.

show abstract

“…It has been proposed that B-raf activity in cells lacking TSC2 may play a role in differentiation but the functional link and its mechanism remain unclear 45 . Alternatively, we have previously reported that the TSC pathway negatively regulates the Wnt/β-catenin pathway by promoting the activity of its degradation complex 46 . β-catenin is known to regulate transcription of crucial genes involved in proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

Self Cite

View full text Add to dashboard Cite

Angiomyolipomata (AML) belong to a family of tumors known as perivascular epithelioid cell tumors (PEComas) that share a common immunophenotypic profile of muscle and melanocytic differentiation. These tumors are clonal in nature and have a strong association with tuberous sclerosis. Genetic analyses have reported allelic imbalance at the TSC2 locus on 16p13. In the context of non-TSC, non-LAM associated AMLs and non-renal PEComas, the functional status of the TSC2 signaling pathway has not been reported. Studies over the last several years have uncovered a critical role of the TSC1/2 genes in negatively regulating the Rheb/mTOR/p70S6K cascade. Here, we examined the activity of this pathway in sporadic AMLs and PEComas using immunohistochemical and biochemical analyses. We found increased levels of phospho-p70S6K, a marker of mTOR activity, in 15 of 15 non-TSC AMLs. This was accompanied by reduced phospho-AKT expression, a pattern that is consistent with the disruption of TSC1/2 function. Western blot analysis confirmed mTOR activation concurrent with the loss of TSC2 and not TSC1 in sporadic AMLs. Similarly, elevated phospho-p70S6K and reduced phospho-AKT expression was detected in 14/15 cases of extra-renal PEComas. These observations provide the first functional evidence that mTOR activation is common to sporadic, non-TSC-related AMLs and PEComas. This suggests the possibility that mTOR inhibitors such as rapamycin may be therapeutic for this class of disease.

show abstract

The Tuberin-Hamartin Complex Negatively Regulates β-Catenin Signaling Activity

Cited by 96 publications

References 26 publications

A signaling loop of REST, TSC2 and β-catenin governs proliferation and function of PC12 neural cells

A signaling loop of REST, TSC2 and β-catenin governs proliferation and function of PC12 neural cells

mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization

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

Contact Info

Product

Resources

About