Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects

Jhanwar‐Uniyal, Meena; Amin, Anubhav G.; Cooper, Jared; Das, Kaushik; Schmidt, Meic H.; Murali, Raj

doi:10.1016/j.jbior.2016.12.001

Cited by 105 publications

(80 citation statements)

References 80 publications

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“…After the initial discovery of mTOR, follow-up studies in yeast and mammalian cells revealed that mTOR forms the catalytic core of two important but functionally distinct multi-protein complexes, mTORC1 and mTORC2, which are composed of both unique and shared components (Figure 1A) (reviewed in [9,11,21]). Specifically, mTORC1 is composed of mTOR in association with two unique regulatory protein subunits, Raptor (rapamycin-sensitive adapter protein of mTOR) and Pras40 (proline-rich AKT substrate 40 kDa), and the shared components mLST8 (mammalian lethal with Sec-13 protein 8), Tti1/Tel2 (Tel2 interacting protein 1/telomere maintenance 2), and Deptor (dep domain continingTOR-interacting protein).…”

Section: Overview Of Mtor Signaling Pathwaysmentioning

confidence: 99%

Control of B lymphocyte development and functions by the mTOR signaling pathways

Iwata

Ramírez-Komo

Park

et al. 2017

Cytokine & Growth Factor Reviews

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Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase originally discovered as the molecular target of the immunosuppressant rapamycin. mTOR forms two compositionally and functionally distinct complexes, mTORC1 and mTORC2, which are crucial for coordinating nutrient, energy, oxygen, and growth factor availability with cellular growth, proliferation, and survival. Recent studies have identified critical, non-redundant roles for mTORC1 and mTORC2 in controlling B cell development, differentiation, and functions, and have highlighted emerging roles of the Folliculin-Fnip protein complex in regulating mTOR and B cell development. In this review, we summarize the basic mechanisms of mTOR signaling; describe what is known about the roles of mTORC1, mTORC2, and the Folliculin/Fnip1 pathway in B cell development and functions; and briefly outline current clinical approaches for targeting mTOR in B cell neoplasms. We conclude by highlighting a few salient questions and future perspectives regarding mTOR in B lineage cells.

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Section: Overview Of Mtor Signaling Pathwaysmentioning

confidence: 99%

Control of B lymphocyte development and functions by the mTOR signaling pathways

Iwata

Ramírez-Komo

Park

et al. 2017

Cytokine & Growth Factor Reviews

View full text Add to dashboard Cite

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“…mTORC1 also has a prominent role in lipid synthesis, required for the generation of cellular membrane during proliferation [67]. Cancer cells often hijack the PI3K/AKT/mTOR pathway in order to meet the demands of increased growth rate, as observed in patients with acute myeloid leukemia [69][70][71].…”

Section: Mtormentioning

confidence: 99%

“…Inactivating mutations in the tumor suppressor gene, PTEN, a phosphatase that antagonizes PI3K function are a common feature in cancer cells [71]. This causes an upregulation of PI3K activity in the cell and constitutive stimulation of the PI3K/AKT/mTOR pathway [42,80].…”

Section: Mtor and Its Role In Cancermentioning

confidence: 99%

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

2017

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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.

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“…S6K and eIF4EBP1 are the most important molecules downstream of EGFR/AKT/ERK that directly regulate protein synthesis and promote cell proliferation (Jhanwar-Uniyal et al 2017). We tested the phosphorylation levels of these molecules in H358 R /A549 R cells after gefitinib combined with cisplatin treatment.…”

Section: Gefitinib Combined With Cisplatin Significantly Inhibits Promentioning

confidence: 99%

Gefitinib sensitization of cisplatin-resistant wild-type EGFR non-small cell lung cancer cells

Cao

Liu

et al. 2020

J Cancer Res Clin Oncol

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Purpose The usual first-line strategy of wild-type EGFR (wtEGFR) non-small cell lung cancer (NSCLC) remains cisplatinbased chemotherapy. However, cisplatin often loses effectiveness because most tumors acquire drug resistance over time. As EGFR is the most important pro-survival/proliferation signal receptor in NSCLC cells, we aimed at investigating whether cisplatin resistance is related to EGFR activation and further evaluating the combined effects of cisplatin/gefitinib (EGFRtyrosine kinase inhibitor, EGFR-TKI) on cisplatin-resistant wtEGFR NSCLC cells. Materials and methods EGFR activation was analysed in parental and cisplatin-resistant wtEGFR NSCLC cell lines (H358 and H358 R , A549 and A549 R ). Cellular proliferation and apoptosis of H358 R /A549 R cells treated with cisplatin or gefitinib, alone or in combination were investigated, and the related effector protein was detected by western blot analysis. Anti-tumor effect of two drugs combined was evaluated in animal models of H358 R xenografts in vivo. Results EGFR was significantly phosphorylated in cisplatin-resistant wtEGFR NSCLC cells H358 R and A549 R than their parental cells. In H358 R and A549 R cells, anti-proliferative ability of gefitinib was further improved, and gefitinib combined with cisplatin enhanced inhibition of cellular survive/proliferation, and promotion of apoptosis in vitro. The combined effects were also associated with the inhibition of EGFR downstream effector proteins. Similarly, in vivo, gefitinib and cisplatin in combination significantly inhibited tumor growth of H358 R xenografts. Conclusion Abnormal activation of EGFR may induce wtEGFR NSCLC cell resistance to cisplatin. The combined effects of cisplatin/gefitinib suggest that gefitinib, as a combination therapy for patients with cisplatin-resistant wtEGFR NSCLC should be considered.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects

Cited by 105 publications

References 80 publications

Control of B lymphocyte development and functions by the mTOR signaling pathways

Control of B lymphocyte development and functions by the mTOR signaling pathways

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

Gefitinib sensitization of cisplatin-resistant wild-type EGFR non-small cell lung cancer cells

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