Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship

Jhanwar‐Uniyal, Meena; Wainwright, John V.; Mohan, Avinash; Tobias, Michael; Murali, Raj; Gandhi, Chirag D.; Schmidt, Meic H.

doi:10.1016/j.jbior.2019.03.003

Cited by 198 publications

(154 citation statements)

References 89 publications

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“…The AKT/ TSC1-TSC2 signalling pathway can also regulate mTOR activity as well as cell growth and proliferation. TSC2 has GTPase activity and inhibits the small GTPase Rheb, which is necessary for mTORC1 activation [59]. Following phosphorylation of TSC2 by AKT, TSC2 loses its ability to inhibit mTORC1 and activate mTOR.…”

Section: Akt Target Proteinsmentioning

confidence: 99%

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RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

et al. 2020

Cell Biosci

453

263

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The PI3 K/AKT/mTOR signalling pathway plays an important role in the regulation of signal transduction and biological processes such as cell proliferation, apoptosis, metabolism and angiogenesis. Compared with those of other signalling pathways, the components of the PI3K/AKT/mTOR signalling pathway are complicated. The regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway are important in many human diseases, including ischaemic brain injury, neurodegenerative diseases, and tumours. PI3K/AKT/mTOR signalling pathway inhibitors include single-component and dual inhibitors. Numerous PI3K inhibitors have exhibited good results in preclinical studies, and some have been clinically tested in haematologic malignancies and solid tumours. In this review, we briefly summarize the results of research on the PI3K/AKT/mTOR pathway and discuss the structural composition, activation, communication processes, regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway in the pathogenesis of neurodegenerative diseases and tumours.

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Section: Akt Target Proteinsmentioning

confidence: 99%

“…Following phosphorylation of TSC2 by AKT, TSC2 loses its ability to inhibit mTORC1 and activate mTOR. In addition, TSC2 can be directly activated by AMPK phosphorylation, and AKT can completely inhibit TSC2 and activate mTOR by inhibiting AMPK [59,60].…”

Section: Akt Target Proteinsmentioning

confidence: 99%

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

et al. 2020

Cell Biosci

453

263

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“…An important pathway in metabolic plasticity is the mammalian target of rapamycin (mTOR) centred signalling regulatory network. mTOR hyperactivation is characteristic for several tumours even for GBMs [15]. However, its regulatory role depends on different complex formation and activity; these complexes differ in their core proteins, targets, functions (including metabolic functions) and inhibitor sensitivities.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Metabolic Shift can Decrease Therapy Resistance in Human High-Grade Glioma Cells

Petővári

Dankó

Krencz

et al. 2019

Pathol. Oncol. Res.

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The high-grade brain malignancy, glioblastoma multiforme (GBM), is one of the most aggressive tumours in central nervous system. The developing resistance against recent therapies and the recurrence rate of GBMs are extremely high. In spite several new ongoing trials, GBM therapies could not significantly increase the survival rate of the patients as significantly. The presence of inter-and intra-tumoral heterogeneity of GBMs arise the problem to find both the pre-existing potential resistant clones and the cellular processes which promote the adaptation mechanisms such as multidrug resistance, stem cell-ness or metabolic alterations, etc. In our work, the in situ metabolic heterogeneity of high-grade human glioblastoma cases were analysed by immunohistochemistry using tissue-microarray. The potential importance of the detected metabolic heterogeneity was tested in three glioma cell lines (grade III-IV) using protein expression analyses (Western blot and WES Simple) and therapeutic drug (temozolomide), metabolic inhibitor treatments (including glutaminase inhibitor) to compare the effects of rapamycin (RAPA) and glutaminase inhibitor combinations in vitro (Alamar Blue and SRB tests). The importance of individual differences and metabolic alterations were observed in mono-therapeutic failures, especially the enhanced Rictor expressions after different monotreatments in correlation to lower sensitivity (temozolomide, doxycycline, etomoxir, BPTES). RAPA combinations with other metabolic inhibitors were the best strategies except for RAPA+glutaminase inhibitor. These observations underline the importance of multi-targeting metabolic pathways. Finally, our data suggest that the detected metabolic heterogeneity (the high mTORC2 complex activity, enhanced expression of Rictor, p-Akt, p-S6, CPT1A, and LDHA enzymes in glioma cases) and the microenvironmental or treatment induced metabolic shift can be potential targets in combination therapy. Therefore, it should be considered to map tissue heterogeneity and alterations with several cellular metabolism markers in biopsy materials after applying recently available or new treatments.

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“…It activates under anabolic conditions that coincide with energy-su cient states and deactivates under catabolic conditions of energy stress. Serine 2448 phosphorylation levels positively correlate with mTOR activity, and suggest a downstream stimulation of mTORC2 and mTORC1, protein complexes implicated in cell metabolic regulation (47,48). Decreased mTOR 2448 phosphorylation in APOE ε4 carrier lymphocytes suggests that allele shifts the anabolic-catabolic balance to a more catabolic setting.…”

Section: Discussionmentioning

confidence: 99%

Blood Bioenergetic Biomarkers in Alzheimer’s Disease APOE ε4-Carriers

Wilkins

Manley

Wang

et al. 2020

Preprint

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Abstract Background:This study examined the impact of APOE ε4 on blood cell bioenergetics. Prior studies have shown systemic alterations in blood cells from APOE ε4 carriers.Methods:Platelet mitochondria cytochrome oxidase (COX) and citrate synthase (CS) Vmax activities were measured in APOE ε4 carrier and non-carrier Alzheimer’s disease (AD) subjects, and lymphocyte mitochondria and bioenergetics-relevant protein and viability endpoints were measured using fresh and expanded cultures. Statistical analysis was completed using Student’s T-Test.Results:The mean platelet COX Vmax activity, normalized to protein content, was lower in APOE ε4 carriers and lymphocyte Annexin V, a marker of apoptosis, was significantly higher. PINK1, a protein involved in mitophagy, was higher in APOE ε4 carrier lymphocytes. mTOR and SIRT1, which play a role in energy sensing, were different between the groups; mTOR phosphorylation decreased while SIRT1 phosphorylation increased in APOE ε4 carrier lymphocytes. The lipid synthesis pathway differed, as AceCSI and ATP CL increased in APOE ε4 carrier lymphocytes, and ACC phosphorylation also increased.Conclusions:These findings overall support a relationship between APOE genotype and bioenergetic pathways and indicate that relative to AD non-APOE ε4 carriers, platelets and lymphocytes from AD APOE ε4 carriers exist in a relative state of bioenergetic stress. As APOE ε4 influences AD risk these data may help define a systemic AD biomarker phenotype.

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Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship

Cited by 198 publications

References 89 publications

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

Inhibition of Metabolic Shift can Decrease Therapy Resistance in Human High-Grade Glioma Cells

Blood Bioenergetic Biomarkers in Alzheimer’s Disease APOE ε4-Carriers

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