mTOR signaling at a glance

Laplante, Mathieu; Sabatini, David M.

doi:10.1242/jcs.051011

Cited by 1,899 publications

(1,911 citation statements)

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“…1 In the central nervous system, mTORC1 signaling is crucial since the early stages of neural development, controlling self-renewal and differentiation of neural progenitor stem cells, [2][3][4] and in neurons, mTORC1-dependent translation is involved in synapse formation and plasticity. 5 Therefore, dysfunctional mTORC1 signaling and dysregulated protein synthesis in neuronal cells have been associated with several neurodevelopmental disorders with intellectual disability and autism.…”

Section: Introductionmentioning

confidence: 99%

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

et al. 2015

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Protein synthesis regulation via mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has key roles in neural development and function, and its dysregulation is involved in neurodevelopmental disorders associated with autism and intellectual disability. mTOR regulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3 complex and by controlling phosphorylation of key translational regulators. Collybistin (CB), a neuronspecific Rho-GEF responsible for X-linked intellectual disability with epilepsy, also interacts with eIF3, and its binding partner gephyrin associates with mTOR. Therefore, we hypothesized that CB also binds mTOR and affects mTORC1 signaling activity in neuronal cells. Here, by using induced pluripotent stem cell-derived neural progenitor cells from a male patient with a deletion of entire CB gene and from control individuals, as well as a heterologous expression system, we describe that CB physically interacts with mTOR and inhibits mTORC1 signaling pathway and protein synthesis. These findings suggest that disinhibited mTORC1 signaling may also contribute to the pathological process in patients with loss-of-function variants in CB.

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Section: Introductionmentioning

confidence: 99%

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

et al. 2015

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“…The current understanding of mTOR is that it nucleates at least two multiprotein complexes, mTORC1 and mTORC2, that direct cell metabolism, growth, proliferation, survival, and tumour angiogenesis. The rapamycin-sensitive mTORC1 essentially mediates phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT/PKB) signals and, through its direct phosphorylation of the ribosomal protein S6 kinase 1 (S6K1) and the eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), promotes many anabolic processes, including biosynthesis of proteins, lipids and organelles, and limits catabolic processes such as autophagy (Guertin and Sabatini, 2007;Laplante and Sabatini, 2009). Signalling through mTORC2 is less well understood, but the S 473 phosphorylation on the AKT kinase by mTORC2 implicates mTOR in acting both upstream and downstream of AKT (Sarbassov et Weiler et al al., 2005).…”

Section: Introductionmentioning

confidence: 99%

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

et al. 2012

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An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.Oncogene advance online publication, Word Count:5,868 words Condensed title:Radiation-enhanced mTOR inhibition in glioblastomaWeiler et al. 2 AbstractA relevant mode of resistance to antiangiogenic and radiotherapy appears to be promotion of tumour cell motility and invasiveness in various cancer types, a process commonly referred to as 'evasive resistance' that may underlie progressive disease and complicates further treatment. Hence, a logical advancement in current oncology consists in optimizing antiangiogenic regimens by identifying suitable complementary strategies, ideally targeting cell motility. Here we report that clinically relevant radiation-enhanced inhibition of the mTOR complexes 1 and 2 exercises such a dual control of angiogenesis and invasiveness independent from PTEN/AKT activation in glioblastoma, a tumour entity that is paradigmatic for both excessive vascular proliferation and cell invasion. This is due to a concerted disrupture of the VEGF/VEGFR-2 signalling axis and likewise suppression of RGS4, which we identified to be a key driver of glioblastoma invasiveness. This combined antiangiogenic/antiinvasive approach might be a promising therapeutic option and warrants further clinical investigation in upfront glioblastoma therapy.Weiler et al.3

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“…In addition to its role in neuritogenesis, mTORC1 is a general regulator of protein synthesis, cell growth and size in many cell types (Laplante and Sabatini 2009). To infer mTORC1/S6K pathway activity during in vitro neuronal development, we cultured cortical neurons from WIP −/− and WT mice as above and determined the S6K phosphorylation level.…”

Section: Resultsmentioning

confidence: 99%

“…To analyze the role of the mTORC1‐S6K pathway (Laplante and Sabatini 2009) in neuritic initiation we used the mTORC1 inhibitor rapamycin, which has been used in previous studies mostly to define the contribution of mTORC1 to neuronal polarization in neurons cultured for more than 3 days (Jaworski et al. 2005; Choi et al.…”

Section: Discussionmentioning

confidence: 99%

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Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities

Franco-Villanueva

Antón

2015

Brain and Behavior

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IntroductionNeuronal morphogenesis is governed mainly by two interconnected processes, cytoskeletal reorganization, and signal transduction. The actin‐binding molecule WIP (Wiskott‐Aldrich syndrome protein [WASP]‐interacting protein) was identified as a negative regulator of neuritogenesis. Although WIP controls activity of the actin‐nucleation‐promoting factor neural WASP (N‐WASP) during neuritic differentiation, its implication in signal transduction remains unknown.MethodsUsing primary neurons from WIP‐deficient and wild‐type mice we did an immunofluorescence, morphometric, and biochemical analysis of the signaling modified by WIP deficiency.ResultsHere, we describe the WIP contribution to the regulation of neuritic elaboration and ramification through modification in phosphorylation levels of several kinases that participate in the mammalian target of rapamycin complex 1 (mTORC1)‐p70S6K (phosphoprotein 70 ribosomal protein S6 kinase, S6K) intracellular signaling pathway. WIP deficiency induces an increase in the number of neuritic bifurcations and filopodial protrusions in primary embryonic neurons. This phenotype is not due to modifications in the activity of the phosphoinositide 3 kinase (PI3K)‐Akt pathway, but to reduced phosphorylation of the S6K residues Ser411 and Thr389. The resulting decrease in kinase activity leads to reduced S6 phosphorylation in the absence of WIP. Incubation of control neurons with pharmacological inhibitors of mTORC1 or Abl, two S6K regulators, conferred a morphology resembling that of WIP‐deficient neurons. Moreover, the preferential co‐distribution of phospho‐S6K with polymerized actin is altered in WIP‐deficient neurons.ConclusionThese experiments identify WIP as a member of a signaling cascade comprised of Abl family kinases, mTORC1 and S6K, which regulates neuron development and specifically, neuritic branching and complexity. Thus, we postulated a new role for WIP protein.

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mTOR signaling at a glance

Cited by 1,899 publications

References 70 publications

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities

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