Regulation of mTORC1 by PI3K signaling

Dibble, Christian C.; Cantley, Lewis C.

doi:10.1016/j.tcb.2015.06.002

Cited by 681 publications

(636 citation statements)

References 153 publications

(295 reference statements)

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“…Growth factors such as insulin-like growth factor 1 (IGF 1) and insulin activate the receptor tyrosine kinases or G-protein coupled receptors, which trigger the lipid kinase phosphatidylinositol-3 kinase (PI3K) (Gupta and Dey, 2012;Dibble and Cantley, 2015). The serine/threonine kinase Akt is one of the key downstream mediators of the PI3K signaling (Hay and Sonenberg, 2004;Long et al, 2005;Zoncu et al, 2011;Gupta and Dey, 2012;Dibble and Cantley, 2015).…”

Section: Rheb Signaling Pathwaymentioning

confidence: 99%

“…The serine/threonine kinase Akt is one of the key downstream mediators of the PI3K signaling (Hay and Sonenberg, 2004;Long et al, 2005;Zoncu et al, 2011;Gupta and Dey, 2012;Dibble and Cantley, 2015). Akt links to the mTOR signaling via the tuberous sclerosis complex protein (TSC complex) and Rheb GTPase.…”

Section: Rheb Signaling Pathwaymentioning

confidence: 99%

“…Hence, the GTP/GDP loading state of Rheb is highly regulated by its GAP, which is controlled by the presence of growth factors ( Figure 1). Rheb binds to its effector 'mammalian target of rapamycin' (mTOR) (Long et al, 2005) and GTPloaded Rheb is required for the activation of mTOR (Inoki et al, 2003;Long et al, 2005;Menon et al, 2014;Dibble and Cantley, 2015). A guanine nucleotide exchange factor (GEF) for Rheb has been identified but the biochemical and cellular relevance is still under discussion (Rehmann et al, 2008;Schöpel et al, 2017).…”

Section: Rheb Signaling Pathwaymentioning

confidence: 99%

“…The TSC2 within the intact TSC complex has a strong binding preference for Rheb-GDP. In the presence of insulin, Akt-mediated phosphorylation of TSC complex causes its dissociation from the lysosomes, hence promoting Rheb and mTORC1 activation ( Benjamin and Hall, 2014;Menon et al, 2014;Dibble and Cantley, 2015). Interestingly, mTORC1 can also be activated at other endo-membranes including peroxisomes and Golgi complex (Flinn et al, 2010;Zhang et al, 2013).…”

Section: Regulation Of Rheb Signaling Pathway By Subcellular Localizamentioning

confidence: 99%

“…Cellular levels of amino acids also mediate the regulation of TSC complex dissociation and activation of mTORC1 at the lysosomes (Benjamin and Hall, 2014;Demetriades et al, 2014;Dibble and Cantley, 2015), yet in a different manner involving the Rag-GTPase (Sancak et al, 2008;Groenewoud and Zwartkruis, 2013). Rag-GTPase-mediated translocation of mTORC1 to the lysosomes, brings it into close proximity of Rheb, which stimulates the kinase activity of mTOR (Sancak et al, 2008;Groenewoud and Zwartkruis, 2013;Demetriades et al, 2014).…”

Section: Regulation Of Rheb Signaling Pathway By Subcellular Localizamentioning

confidence: 99%

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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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Section: Rheb Signaling Pathwaymentioning

confidence: 99%

Section: Rheb Signaling Pathwaymentioning

confidence: 99%

Section: Rheb Signaling Pathwaymentioning

confidence: 99%

Section: Regulation Of Rheb Signaling Pathway By Subcellular Localizamentioning

confidence: 99%

Section: Regulation Of Rheb Signaling Pathway By Subcellular Localizamentioning

confidence: 99%

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Rheb in neuronal degeneration, regeneration, and connectivity

Potheraveedu

Schöpel

Stoll

et al. 2017

Biological Chemistry

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Clinical Characteristics of Connective Tissue Nevi in Tuberous Sclerosis Complex With Special Emphasis on Shagreen Patches

et al. 2017

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IMPORTANCE Patients with tuberous sclerosis complex (TSC) frequently develop collagenous connective tissue nevi. The prototypical lesion is a large shagreen patch located on the lower back, but some patients only manifest small collagenomas or have lesions elsewhere on the body. The ability to recognize these variable presentations can be important for the diagnosis of TSC.OBJECTIVE To describe the clinical characteristics of connective tissue nevi on the trunk and extremities of patients with tuberous sclerosis complex. DESIGN, SETTING, AND PARTICIPANTSA retrospective analysis of patient medical records and skin photography was performed; 104 adult patients with TSC were enrolled in an observational cohort study that was enriched for those with pulmonary lymphangioleiomyomatosis, and was therefore composed mostly of women (99 women, 5 men). All patients included were examined at the National Institutes of Health (NIH) in Bethesda, Maryland, from 1998 to 2013. Connective tissue nevi were categorized per anatomic location and size. Lesions less than 1 cm in diameter were termed collagenomas. Shagreen patches were characterized as small (1 to <4 cm), medium (4 to <8 cm), and large (Ն8 cm). MAIN OUTCOME AND MEASURESFrequency, anatomic location, size, and histological appearance of connective tissue nevi in patients with TSC.RESULTS Overall, 58 of 104 patients (median [range] age, 42 [19-70] years) with TSC (56%) had at least 1 connective tissue nevus on the trunk or thighs; of these, 28 of 58 patients (48%) had a solitary lesion, and 30 of 58 patients (52%) had 2 or more lesions. Overall, 120 lesions from 55 patients were classified by size; 46 lesions (38%) were collagenomas; 39 lesions (32%) were small shagreen patches; 21 lesions (18%), medium shagreen patches; and 14 lesions (12%), large shagreen patches. The distribution of lesions was 9% (n = 11), upper back; 29% (n = 35), middle back; 51% (n = 61), lower back; and 11% (n = 13), other locations. All 26 shagreen patches that were analyzed histopathologically had coarse collagen fibers and 24 of 26 stained with Miller elastic stain had decreased elastic fibers. On immunoblot analysis, fibroblasts grown from shagreen patches expressed higher levels of phosphorylated ribosomal protein S6 than paired fibroblasts from normal-appearing skin.CONCLUSIONS AND RELEVANCE Tuberous sclerosis complex-related connective tissue nevi are not limited to the lower back, and occasionally present on the central or upper back, buttocks, or thighs. Elastic fibers are typically decreased. Recognition of these variable presentations can be important for TSC diagnosis.

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NMR analysis of the backbone dynamics of the small GTPase Rheb and its interaction with the regulatory protein FKBP38

2017

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Ras homolog enriched in brain (Rheb) is a small GTPase that regulates mammalian/mechanistic target of rapamycin complex 1 (mTORC1) and, thereby, cell growth and metabolism. Here we show that cycling between the inactive GDP‐ and the active GTP‐bound state modulates the backbone dynamics of a C‐terminal truncated form, RhebΔCT, which is suggested to influence its interactions. We further investigated the interactions between RhebΔCT and the proposed Rheb‐binding domain of the regulatory protein FKBP38. The observed weak interactions with the GTP‐analogue‐ (GppNHp‐) but not the GDP‐bound state, appear to accelerate the GDP to GTP exchange, but only very weakly compared to a genuine GEF. Thus, FKBP38 is most likely not a GEF but a Rheb effector that may function in membrane targeting of Rheb.

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Regulation of mTORC1 by PI3K signaling

Cited by 681 publications

References 153 publications

Rheb in neuronal degeneration, regeneration, and connectivity

Rheb in neuronal degeneration, regeneration, and connectivity

Clinical Characteristics of Connective Tissue Nevi in Tuberous Sclerosis Complex With Special Emphasis on Shagreen Patches

NMR analysis of the backbone dynamics of the small GTPase Rheb and its interaction with the regulatory protein FKBP38

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