TOR Complexes and the Maintenance of Cellular Homeostasis

Eltschinger, Sandra; Loewith, Robbie

doi:10.1016/j.tcb.2015.10.003

Cited by 176 publications

(166 citation statements)

References 100 publications

Supporting

Mentioning

164

Contrasting

Order By: Relevance

“…TORC1 acts by controlling three major cell components: the kinase Sch9, Tap42, its associated phosphatases and the ATG1 complex1415. Active TORC1 directly phosphorylates Sch9 -the orthologue of the mammalian S6 kinase-, which induces RiBi genes, such as STM1 and NSR1 , to increase translation and promote growth (Fig.…”

Section: Discussionmentioning

confidence: 99%

The effector AWR5 from the plant pathogen Ralstonia solanacearum is an inhibitor of the TOR signalling pathway

Popa

Espeso-Gil

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Bacterial pathogens possess complex type III effector (T3E) repertoires that are translocated inside the host cells to cause disease. However, only a minor proportion of these effectors have been assigned a function. Here, we show that the T3E AWR5 from the phytopathogen Ralstonia solanacearum is an inhibitor of TOR, a central regulator in eukaryotes that controls the switch between cell growth and stress responses in response to nutrient availability. Heterologous expression of AWR5 in yeast caused growth inhibition and autophagy induction coupled to massive transcriptomic changes, unmistakably reminiscent of TOR inhibition by rapamycin or nitrogen starvation. Detailed genetic analysis of these phenotypes in yeast, including suppression of AWR5-induced toxicity by mutation of CDC55 and TPD3, encoding regulatory subunits of the PP2A phosphatase, indicated that AWR5 might exert its function by directly or indirectly inhibiting the TOR pathway upstream PP2A. We present evidence in planta that this T3E caused a decrease in TOR-regulated plant nitrate reductase activity and also that normal levels of TOR and the Cdc55 homologues in plants are required for R. solanacearum virulence. Our results suggest that the TOR pathway is a bona fide T3E target and further prove that yeast is a useful platform for T3E function characterisation.

show abstract

Section: Discussionmentioning

confidence: 99%

The effector AWR5 from the plant pathogen Ralstonia solanacearum is an inhibitor of the TOR signalling pathway

Popa

Espeso-Gil

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…mTORC2 is thought to be involved in cell survival and cell-cycle progression through phosphorylation of Ser473 on AKT, and through activation of serum-and SGK and PKC [9,62,67,75]. Recent advancements, in yeast, using reverse chemical genetics have allowed specific mTORC2 inhibition, although an analogous system in mammalian cells has yet to be established [77]. Genetic studies involving the deletion of the RICTOR subunit, an essential scaffold protein, results in mTORC2 disassembly and loss of function.…”

Section: Mtormentioning

confidence: 99%

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

2017

View full text Add to dashboard Cite

Targeting the translational machinery has emerged as a promising therapeutic option for cancer treatment. Cancer cells require elevated protein synthesis and exhibit augmented activity to meet the increased metabolic demand. Eukaryotic translation initiation factor 4E is necessary for mRNA translation, its availability and phosphorylation are regulated by the PI3K/AKT/mTOR and MNK1/2 pathways. The phosphorylated form of eIF4E drives the expression of oncogenic proteins including those involved in metastasis. In this article, we will review the role of eIF4E in cancer, its regulation and discuss the benefit of dual inhibition of upstream pathways. The discernible interplay between the MNK and mTOR signaling pathways provides a novel therapeutic opportunity to target aggressive migratory cancers through the development of hybrid molecules.

show abstract

“…Rags are atypical members of Ras-related GTPases and function as obligate heterodimers composed of RagA or RagB (A/B) and RagC or RagD (C/D). A combination of GTP-RagA/B and GDP-RagC/D is thought to activate mTORC1 by recruiting it to lysosomes (reviewed in Eltschinger and Loewith, 2016). Actually, RagC/D inactivation by the FLCN-FNIP2 complex has clearly been shown to promote mTORC1 binding to Rags in vitro, although the spatiotemporal regulatory mechanism by which FLCN-FNIP1/2 inactivates RagC/D within cells is (Yoshimura et al, 2010) 1 4 -adaptin, clathrin heavy chain, endophilin A1, intersectin, NECAP (Marat et al, 2011) C. elegans rme-4 mutant (Sato et al, 2008) DENND1B (163486) connecdenn 2 Rab35 2,3 (Yoshimura et al, 2010) 1 -adaptin, AP2 2, clathrin heavy chain (Marat et al, 2011) Dennd1b KO mice (Yang et al, 2016) DENND1C (79958) connecdenn 3 Rab35 2,3…”

Section: Denn and Denn-related Proteinsmentioning

confidence: 99%

Multiple Types of Guanine Nucleotide Exchange Factors (GEFs) for Rab Small GTPases

Ishida

Oguchi

Fukuda

2016

Cell Struct. Funct.

View full text Add to dashboard Cite

ABSTRACT. Rab small GTPases are highly conserved master regulators of membrane traffic in all eukaryotes. The same as the activation and inactivation of other small GTPases, the activation and inactivation of Rabs are tightly controlled by specific GEFs (guanine nucleotide exchange factors) and GAPs (GTPase-activating proteins), respectively. Although almost all Rab-GAPs reported thus far have a TBC (Tre-2/Bub2/Cdc16)/Rab-GAP domain in common, recent accumulating evidence has indicated the existence of a number of structurally unrelated types of Rab-GEFs, including DENN proteins, VPS9 proteins, Sec2 proteins, TRAPP complexes, heterodimer GEFs (Mon1-Ccz1, HPS1-HPS4 (BLOC-3 complex), Ric1-Rgp1 and Rab3GAP1/2), and other GEFs (e.g., REI-1 and RPGR). In this review article we provide an up-to-date overview of the structures and functions of all putative Rab-GEFs in mammals, with a special focus on their substrate Rabs, interacting proteins, associations with genetic diseases, and intracellular localizations.

show abstract

TOR Complexes and the Maintenance of Cellular Homeostasis

Cited by 176 publications

References 100 publications

The effector AWR5 from the plant pathogen Ralstonia solanacearum is an inhibitor of the TOR signalling pathway

The effector AWR5 from the plant pathogen Ralstonia solanacearum is an inhibitor of the TOR signalling pathway

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

Multiple Types of Guanine Nucleotide Exchange Factors (GEFs) for Rab Small GTPases

Contact Info

Product

Resources

About