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Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis.

Neuman NA, Henske EP - EMBO Mol Med (2011)

Bottom Line: The vast majority of research regarding these proteins has focused on mammalian Target of Rapamycin (mTOR), a target of Rheb.Here, we propose that there are clinically relevant functions and targets of TSC1, TSC2 and Rheb, which are independent of mTOR.We present evidence that such non-canonical functions of the TSC-Rheb signalling network exist, propose a standard of evidence for these non-canonical functions, and discuss their potential clinical and therapeutic implications for patients with TSC and lymphangioleiomyomatosis (LAM).

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

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Related in: MedlinePlus

Cell physiological functions of non-canonical TSC-Rheb signallingTSC1- and TSC2-mutant cells display increased primary cilium number and length (1) that is not restored by Rapamycin treatment. As TSC1 localizes to the centrosome at the basal body of the cilium (shown in purple), it is possible that TSC1 regulates primary cilium formation through a centrosome-dependent process. Active Rheb induces Notch signalling (2) through a Rapamycin- and TOR kinase inhibitor-insensitive mechanism. TSC1 and TSC2 have also been shown to regulate the actin cytoskeleton (3) through Rho-dependent, TORC1-independent mechanisms, likely involving both TORC2 and other mediators. Active Rheb also suppresses formation of the aggresome (4), another centrosome-dependent process, through a TORC1-independent process.
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fig04: Cell physiological functions of non-canonical TSC-Rheb signallingTSC1- and TSC2-mutant cells display increased primary cilium number and length (1) that is not restored by Rapamycin treatment. As TSC1 localizes to the centrosome at the basal body of the cilium (shown in purple), it is possible that TSC1 regulates primary cilium formation through a centrosome-dependent process. Active Rheb induces Notch signalling (2) through a Rapamycin- and TOR kinase inhibitor-insensitive mechanism. TSC1 and TSC2 have also been shown to regulate the actin cytoskeleton (3) through Rho-dependent, TORC1-independent mechanisms, likely involving both TORC2 and other mediators. Active Rheb also suppresses formation of the aggresome (4), another centrosome-dependent process, through a TORC1-independent process.

Mentions: The primary cilium consists of a finger-like plasma membrane projection, reinforced by an internal stalk of microtubule bundles with a centriole anchoring its base (Goetz & Anderson, 2010). These cilia transmit signals about extracellular flow and are epicenters for certain signal transduction pathways such as Hedgehog signalling. TSC1 is present at the base of the primary cilium in cultured human retinal pigmented and kidney epithelial cells (Fig 4; Astrinidis et al, 2006; Hartman et al, 2009). Interestingly, Tsc1−/− and Tsc2−/− mouse embryonic fibroblasts (MEFs) have longer cilia, and a greater percentage of cells in culture are single- or multi-ciliated compared to wild-type (WT) MEFs, suggesting that the TSC1/TSC2 complex suppresses cilia formation (Hartman et al, 2009). Importantly, Rapamycin treatment restores cilia length in some, but not all, cell lines tested, and it does not reduce the frequency of ciliation in MEFs. Taken together, this could indicate that non-canonical functions of TSC1 and TSC2 are important for ciliary phenotypes.


Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis.

Neuman NA, Henske EP - EMBO Mol Med (2011)

Cell physiological functions of non-canonical TSC-Rheb signallingTSC1- and TSC2-mutant cells display increased primary cilium number and length (1) that is not restored by Rapamycin treatment. As TSC1 localizes to the centrosome at the basal body of the cilium (shown in purple), it is possible that TSC1 regulates primary cilium formation through a centrosome-dependent process. Active Rheb induces Notch signalling (2) through a Rapamycin- and TOR kinase inhibitor-insensitive mechanism. TSC1 and TSC2 have also been shown to regulate the actin cytoskeleton (3) through Rho-dependent, TORC1-independent mechanisms, likely involving both TORC2 and other mediators. Active Rheb also suppresses formation of the aggresome (4), another centrosome-dependent process, through a TORC1-independent process.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3377068&req=5

fig04: Cell physiological functions of non-canonical TSC-Rheb signallingTSC1- and TSC2-mutant cells display increased primary cilium number and length (1) that is not restored by Rapamycin treatment. As TSC1 localizes to the centrosome at the basal body of the cilium (shown in purple), it is possible that TSC1 regulates primary cilium formation through a centrosome-dependent process. Active Rheb induces Notch signalling (2) through a Rapamycin- and TOR kinase inhibitor-insensitive mechanism. TSC1 and TSC2 have also been shown to regulate the actin cytoskeleton (3) through Rho-dependent, TORC1-independent mechanisms, likely involving both TORC2 and other mediators. Active Rheb also suppresses formation of the aggresome (4), another centrosome-dependent process, through a TORC1-independent process.
Mentions: The primary cilium consists of a finger-like plasma membrane projection, reinforced by an internal stalk of microtubule bundles with a centriole anchoring its base (Goetz & Anderson, 2010). These cilia transmit signals about extracellular flow and are epicenters for certain signal transduction pathways such as Hedgehog signalling. TSC1 is present at the base of the primary cilium in cultured human retinal pigmented and kidney epithelial cells (Fig 4; Astrinidis et al, 2006; Hartman et al, 2009). Interestingly, Tsc1−/− and Tsc2−/− mouse embryonic fibroblasts (MEFs) have longer cilia, and a greater percentage of cells in culture are single- or multi-ciliated compared to wild-type (WT) MEFs, suggesting that the TSC1/TSC2 complex suppresses cilia formation (Hartman et al, 2009). Importantly, Rapamycin treatment restores cilia length in some, but not all, cell lines tested, and it does not reduce the frequency of ciliation in MEFs. Taken together, this could indicate that non-canonical functions of TSC1 and TSC2 are important for ciliary phenotypes.

Bottom Line: The vast majority of research regarding these proteins has focused on mammalian Target of Rapamycin (mTOR), a target of Rheb.Here, we propose that there are clinically relevant functions and targets of TSC1, TSC2 and Rheb, which are independent of mTOR.We present evidence that such non-canonical functions of the TSC-Rheb signalling network exist, propose a standard of evidence for these non-canonical functions, and discuss their potential clinical and therapeutic implications for patients with TSC and lymphangioleiomyomatosis (LAM).

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Show MeSH
Related in: MedlinePlus