Non‐canonical functions of the tuberous sclerosis complex‐Rheb signalling axis

Neuman, Nicole; Henske, Elizabeth P.

doi:10.1002/emmm.201100131

Cited by 79 publications

(80 citation statements)

References 103 publications

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“…We previously found that suppression of Rheb-GTPase activity with farnesyl transferase inhibitors almost completely rescued spine synapse formation 14 . Thus, a non-canonical pathway such as this Rheb-syntenin signalling may participate in some of the symptomatic manifestations in TSC [40][41][42] . Indeed, knockdown and knockout of brain syntenin restored contextual fear discrimination deficits in Tsc2 þ / À rats and mice, respectively (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

et al. 2015

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Rheb is a small GTP-binding protein and its GTPase activity is activated by the complex of Tsc1 and Tsc2 whose mutations cause tuberous sclerosis complex (TSC). We previously reported that cultured TSC neurons showed impaired spine synapse morphogenesis in an mTORC1-independent manner. Here we show that the PDZ protein syntenin preferentially binds to the GDP-bound form of Rheb. The levels of syntenin are significantly higher in TSC neurons than in wild-type neurons because the Rheb-GDP-syntenin complex is prone to proteasomal degradation. Accumulated syntenin in TSC neurons disrupts spine synapse formation through inhibition of the association between syndecan-2 and calcium/calmodulindependent serine protein kinase. Instead, syntenin enhances excitatory shaft synapse formation on dendrites by interacting with ephrinB3. Downregulation of syntenin in TSC neurons restores both spine and shaft synapse densities. These findings suggest that Rheb-syntenin signalling may be a novel therapeutic target for abnormalities in spine and shaft synapses in TSC neurons.

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Section: Discussionmentioning

confidence: 99%

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

et al. 2015

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“…TSC1 and TSC2 mutations are responsible for tuberous sclerosis and are associated with other diseases including pulmonary lymphangioleiomyomatosis 23 . 3D structures of TSC1, TSC2 and their complex are crucial for understanding their normal function and regulation and the pathogenic mechanism of their mutations.…”

Section: Discussionmentioning

confidence: 99%

“…TSC1 protein has many binding partners in addition to TSC2, and is essential for mouse embryonic development [22][23][24] . Recently, it has been shown that TSC1 has critical roles in neurodevelopment and neurological diseases, immune diseases, diabetes, autophagy and DNA repair [25][26][27][28] .…”

mentioning

confidence: 99%

Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations

et al. 2013

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Tuberous sclerosis complex is a disease caused by mutations in two tumor-suppressor genes, TSC1 and TSC2. The TSC1 protein, also known as hamartin, has a critical role in controlling mTOR signalling. TSC1 does not bear apparent sequence homology with other proteins. Here we show that the N-terminal half of yeast TSC1 forms a protease-resistant domain, which is evolutionarily conserved. The crystal structure of this yeast TSC1 core domain shows that it contains a pseudo-HEAT repeat fold with its C-terminal end capped by a helical subdomain. This allows us to model the three-dimensional structure of the human TSC1 N-terminal domain (TSC1-NTD), which anchors essentially all pathogenic TSC1 missense mutations found in tuberous sclerosis patients. Interestingly, most pathogenic mutations map inside of the folded TSC1-NTD structure, whereas most non-pathogenic variants are on the structural surface. This indicates that the disruption of the TSC1-NTD globular structure is a major cause of tuberous sclerosis.

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“…Recently, several signaling pathways of TSC complex and Rheb have been described that function independently of mTORC1 (Jacinto et al, 2004;Karbowniczek et al, 2006;Zhou et al, 2009;Neuman and Henske, 2011). Hence, the activation of these non-canonical pathways cause some of the clinical manifestations of TSC that are resistant to mTORC1 inhibition by rapamycin (Yasuda et al, 2014).…”

Section: Non-canonical Rheb Pathwaymentioning

confidence: 99%

Rheb in neuronal degeneration, regeneration, and connectivity

Potheraveedu

Schöpel

Stoll

et al. 2017

Biological Chemistry

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Abstract:The small GTPase Rheb was originally detected as an immediate early response protein whose expression was induced by NMDA-dependent synaptic activity in the brain. Rheb's activity is highly regulated by its GTPase activating protein (GAP), the tuberous sclerosis complex protein, which stimulates the conversion from the active, GTP-loaded into the inactive, GDP-loaded conformation. Rheb has been established as an evolutionarily conserved molecular switch protein regulating cellular growth, cell volume, cell cycle, autophagy, and amino acid uptake. The subcellular localization of Rheb and its interacting proteins critically regulate its activity and function. In stem cells, constitutive activation of Rheb enhances differentiation at the expense of self-renewal partially explaining the adverse effects of deregulated Rheb in the mammalian brain. In the context of various cellular stress conditions such as oxidative stress, ER-stress, death factor signaling, and cellular aging, Rheb activation surprisingly enhances rather than prevents cellular degeneration. This review addresses cell type-and cell state-specific function(s) of Rheb and mainly focuses on neurons and their surrounding glial cells. Mechanisms will be discussed in the context of therapy that interferes with Rheb's activity using the antibiotic rapamycin or low molecular weight compounds.

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Non‐canonical functions of the tuberous sclerosis complex‐Rheb signalling axis

Cited by 79 publications

References 103 publications

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations

Rheb in neuronal degeneration, regeneration, and connectivity

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