Autophagy and receptor tyrosine kinase signalling: A mTORC2 matter

Lampada, Aikaterini; Hochhauser, Daniel; Salomoni, Paolo

doi:10.1080/15384101.2017.1372548

Cited by 8 publications

(8 citation statements)

References 7 publications

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“…IGF‐1 can inhibit autophagy via activation of mTORC2 and AKT, linking glucose metabolism as a nutritional cue able to modulate autophagy processes through these proteins (Wang & Gu, 2018 ). In colorectal cancer cells with constitutively activated mTORC1, mTORC2 appears to regulate the levels of basal autophagy and participate in the maintenance of signaling vesicles and tumor cell survival (Lampada et al, 2017 , 2017 ).…”

Section: Mtorc2: the Other Mtormentioning

confidence: 99%

mTORC2: The other mTOR in autophagy regulation

2021

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The mechanistic target of rapamycin (mTOR) has gathered significant attention as a ubiquitously expressed multimeric kinase with key implications for cell growth, proliferation, and survival. This kinase forms the central core of two distinct complexes, mTORC1 and mTORC2, which share the ability of integrating environmental, nutritional, and hormonal cues but which regulate separate molecular pathways that result in different cellular responses. Particularly, mTORC1 has been described as a major negative regulator of endosomal biogenesis and autophagy, a catabolic process that degrades intracellular components and organelles within the lysosomes and is thought to play a key role in human health and disease. In contrast, the role of mTORC2 in the regulation of autophagy has been considerably less studied despite mounting evidence this complex may regulate autophagy in a different and perhaps complementary manner to that of mTORC1. Genetic ablation of unique subunits is currently being utilized to study the differential effects of the two mTOR complexes. RICTOR is the best‐described subunit specific to mTORC2 and as such has become a useful tool for investigating the specific actions of this complex. The development of complex‐specific inhibitors for mTORC2 is also an area of intense interest. Studies to date have demonstrated that mTORC1/2 complexes each signal to a variety of exclusive downstream molecules with distinct biological roles. Pinpointing the particular effects of these downstream effectors is crucial toward the development of novel therapies aimed at accurately modulating autophagy in the context of human aging and disease.

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Section: Mtorc2: the Other Mtormentioning

confidence: 99%

mTORC2: The other mTOR in autophagy regulation

2021

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“…Aspernig et al found that the inactivation of mTORC2-SGK-1 (serum/glucocorticoid regulated kinase 1, SGK-1) signaling impairs mitochondrial homeostasis and triggers the increased release of mitochondria-derived reactive oxygen species (mtROS) to induce autophagy [ 45 ]. In the study by Lampada et al, genetic inhibition of mTORC2 and pharmacological inhibition of both mTORC1/2 led to decreased phosphorylation of c-MET, one of the receptor tyrosine kinases, in autophagy-proficient but not autophagy-impaired cells [ 46 ]. Olanzapine, an autophagy activator, protects neurons from fatal mitochondrial damage [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Alteration in the mRNA expression profile of the autophagy-related mTOR pathway in schizophrenia patients treated with olanzapine

Cui

et al. 2021

BMC Psychiatry

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Background The mammalian target of rapamycin protein (mTOR) signaling pathway is involved in the pathogenesis of schizophrenia and the mechanism of extrapyramidal adverse reactions to antipsychotic drugs, which might be mediated by an mTOR-dependent autophagy impairment. This study aimed to examine the expression of mTOR pathway genes in patients with schizophrenia treated with olanzapine, which is considered an mTOR inhibitor and autophagy inducer. Methods Thirty-two patients with acute schizophrenia who had been treated with olanzapine for four weeks (average dose 14.24 ± 4.35 mg/d) and 32 healthy volunteers were recruited. Before and after olanzapine treatment, the Positive and Negative Syndrome Scale (PANSS) was used to evaluate the symptoms of patients with schizophrenia, and the mRNA expression levels of mTOR pathway-related genes, including MTOR, RICTOR, RAPTOR, and DEPTOR, were detected in fasting venous blood samples from all subjects using real-time quantitative PCR. Results The MTOR and RICTOR mRNA expression levels in patients with acute schizophrenia were significantly decreased compared with those of healthy controls and further significantly decreased after four weeks of olanzapine treatment. The DEPTOR mRNA expression levels in patients with acute schizophrenia were not significantly different from those of healthy controls but were significantly increased after treatment. The expression levels of the RAPTOR mRNA were not significantly different among the three groups. The pairwise correlations of MTOR, DEPTOR, RAPTOR, and RICTOR mRNA expression levels in patients with acute schizophrenia and healthy controls were significant. After olanzapine treatment, the correlations between the expression levels of the DEPTOR and MTOR mRNAs and between the DEPTOR and RICTOR mRNAs disappeared. Conclusions Abnormalities in the mTOR pathway, especially DEPTOR and mTORC2, might play important roles in the autophagy mechanism underlying the pathophysiology of schizophrenia and effects of olanzapine treatment.

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“…Several signaling pathways triggered after activations of RTKs are known regulators of the autophagic process, i.e. mTOR 33 , thus RTKs inhibition can have a direct impact over autophagy regulation. Accordingly, suppression of GluIIβ activity either by a selective inhibitor or siRNA technology has been repeatedly reported to cause an induction of autophagy 4,5 , which may additionally be support by our finding that knock-out of GluIIβ down-regulated multiple RTK signaling activities leading to autophagy.…”

Section: Discussionmentioning

confidence: 99%

Knockout of glucosidase II beta subunit inhibits growth and metastatic potential of lung cancer cells by inhibiting receptor tyrosine kinase activities

Khaodee

Udomsom

Kunnaja

et al. 2019

Sci Rep

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Glucosidase II (GluII) plays a major role in regulating post-translation modification of N-linked glycoproteins. We have previously reported that the expression of glucosidase II beta subunit (GluIIβ) was significantly increased in lung tumor tissues and its suppression triggers autophagy and/or apoptosis. Here, we investigated the role of GluIIβ in cell growth, metastatic potential, and receptor tyrosine kinases (RTKs) signaling activity in lung carcinoma cell lines. CRISPR-CAS9 technology was used to knockout the GluIIβ encoding gene (PRKSH) in lung carcinoma cells. GluIIβ knockout cells exhibited drastically slower growth rates in comparison to non-target transfected cells, particularly with lower concentrations of fetal bovine serum, indicating impairment of their ability to survive under nutritional deprivation. Cell migration and anchorage-independent growth, the fundamental components of cancer cell metastasis, were significantly decreased in GluIIβ knockout cells. Knockout of GluIIβ increased the sensitivity of lung cancer cells to cisplatin but reduced their sensitivity to gefitinib. Interestingly, knocking out of GluIIβ lowered overall RTK signaling activities to less than half of those in non-target transfected cells, which could represent a novel strategy for blocking multiple RTKs in tumor cells in an effort to improve lung cancer treatment.

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Autophagy and receptor tyrosine kinase signalling: A mTORC2 matter

Cited by 8 publications

References 7 publications

mTORC2: The other mTOR in autophagy regulation

mTORC2: The other mTOR in autophagy regulation

Alteration in the mRNA expression profile of the autophagy-related mTOR pathway in schizophrenia patients treated with olanzapine

Knockout of glucosidase II beta subunit inhibits growth and metastatic potential of lung cancer cells by inhibiting receptor tyrosine kinase activities

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