scholarly journals mTOR Regulation of Metabolism in Hematologic Malignancies

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 404 ◽  
Author(s):  
Simone Mirabilii ◽  
Maria Rosaria Ricciardi ◽  
Agostino Tafuri
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Selective Advantage ◽  
Hematologic Malignancies ◽  
Therapeutic Agents ◽  
Serine Threonine Kinase ◽  
Normal Cells ◽  
Threonine Kinase ◽  
Metabolic Phenotypes ◽  
Regulation Of Metabolism ◽  
Tumor Types

Neoplastic cells rewire their metabolism, acquiring a selective advantage over normal cells and a protection from therapeutic agents. The mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase involved in a variety of cellular activities, including the control of metabolic processes. mTOR is hyperactivated in a large number of tumor types, and among them, in many hematologic malignancies. In this article, we summarized the evidence from the literature that describes a central role for mTOR in the acquisition of new metabolic phenotypes for different hematologic malignancies, in concert with other metabolic modulators (AMPK, HIF1α) and microenvironmental stimuli, and shows how these features can be targeted for therapeutic purposes.

scholarly journals mTOR Signaling in Metabolism and Cancer

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2278
Author(s):  
Shile Huang
Keyword(s):  
Physiological Activity ◽  
Mammalian Target Of Rapamycin ◽  
Hematologic Malignancies ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Promising Strategy ◽  
Different Types ◽  
And Function

The mechanistic/mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a central regulator for human physiological activity. Deregulated mTOR signaling is implicated in a variety of disorders, such as cancer, obesity, diabetes, and neurodegenerative diseases. The papers published in this special issue summarize the current understanding of the mTOR pathway and its role in the regulation of tissue regeneration, regulatory T cell differentiation and function, and different types of cancer including hematologic malignancies, skin, prostate, breast, and head and neck cancer. The findings highlight that targeting the mTOR pathway is a promising strategy to fight against certain human diseases.

scholarly journals Ubiquitin Hydrolase UCH-L1 Destabilizes mTOR Complex 1 by Antagonizing DDB1-CUL4-Mediated Ubiquitination of Raptor

2013 ◽  
Vol 33 (6) ◽  
pp. 1188-1197 ◽  
Author(s):  
Sajjad Hussain ◽  
Andrew L. Feldman ◽  
Chittaranjan Das ◽  
Steven C. Ziesmer ◽  
Stephen M. Ansell ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Biological Functions ◽  
Serine Threonine Kinase ◽  
Normal Cells ◽  
S6 Kinase ◽  
Threonine Kinase ◽  
Ubiquitin Ligase Complex ◽  
Mtor Complex 1

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates processes including mRNA translation, proliferation, and survival. By assembling with different cofactors, mTOR forms two complexes with distinct biological functions. Raptor-bound mTOR (mTORC1) governs cap-dependent mRNA translation, whereas mTOR, rictor, and mSin1 (mTORC2) activate the survival and proliferative kinase Akt. How the balance between the competing needs for mTORC1 and -2 is controlled in normal cells and deregulated in disease is poorly understood. Here, we show that the ubiquitin hydrolase UCH-L1 regulates the balance of mTOR signaling by disrupting mTORC1. We find that UCH-L1 impairs mTORC1 activity toward S6 kinase and 4EBP1 while increasing mTORC2 activity toward Akt. These effects are directly attributable to a dramatic rearrangement in mTOR complex assembly. UCH-L1 disrupts a complex between the DDB1-CUL4 ubiquitin ligase complex and raptor and counteracts DDB1-CUL4-mediated raptor ubiquitination. These events lead to mTORC1 dissolution and a secondary increase in mTORC2. Experiments inUchl1-deficient and transgenic mice suggest that the balance between these pathways is important for preventing neurodegeneration and the development of malignancy. These data establish UCH-L1 as a key regulator of the dichotomy between mTORC1 and mTORC2 signaling.

The serine/threonine kinase ULK1 is a target of multiple phosphorylation events

2011 ◽  
Vol 440 (2) ◽  
pp. 283-291 ◽  
Author(s):  
Markus Bach ◽  
Mark Larance ◽  
David E. James ◽  
Georg Ramm
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Phosphorylation Site ◽  
Degradation Process ◽  
Dominant Negative ◽  
Serine Threonine Kinase ◽  
Kinase Activation ◽  
Threonine Kinase ◽  
Convergence Point ◽  
Mtor Phosphorylation

Autophagy is a cellular degradation process that is up-regulated upon starvation. Nutrition-dependent regulation of mTOR (mammalian target of rapamycin) is a major determinant of autophagy. RTK (receptor tyrosine kinase) signalling and AMPK (AMP-activated protein kinase) converge upon mTOR to suppress or activate autophagy. Nutrition-dependent regulation of autophagy is mediated via mTOR phosphorylation of the serine/threonine kinase ULK1 (unc51-like kinase 1). In the present study, we also describe ULK1 as an mTOR-independent convergence point for AMPK and RTK signalling. We initially identified ULK1 as a 14-3-3-binding protein and this interaction was enhanced by treatment with AMPK agonists. AMPK interacted with ULK1 and phosphorylated ULK1 at Ser555in vitro. Mutation of this residue to alanine abrogated 14-3-3 binding to ULK1, and in vivo phosphorylation of ULK1 was blocked by a dominant-negative AMPK mutant. We next identified a high-stringency Akt site in ULK1 at Ser774 and showed that phosphorylation at this site was increased by insulin. Finally, we found that the kinase-activation loop of ULK1 contains a consensus phosphorylation site at Thr180 that is required for ULK1 autophosphorylation activity. Collectively, our results suggest that ULK1 may act as a major node for regulation by multiple kinases including AMPK and Akt that play both stimulatory and inhibitory roles in regulating autophagy.

Retinol binding protein 4 affects the adipogenesis of porcine preadipocytes through insulin signaling pathways

2013 ◽  
Vol 91 (4) ◽  
pp. 236-243 ◽  
Author(s):  
Jia Cheng ◽  
Zi-Yi Song ◽  
Lei Pu ◽  
Hao Yang ◽  
Jia-Meng Zheng ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Insulin Signaling ◽  
Binding Protein ◽  
Mammalian Target Of Rapamycin ◽  
Suppressive Effect ◽  
Retinol Binding Protein ◽  
Serine Threonine Kinase ◽  
Retinol Binding Protein 4 ◽  
Threonine Kinase

Retinol binding protein 4 (RBP4), a novel cytokine, is mainly secreted by hepatocytes and adipocytes. RBP4 reportedly induces insulin resistance and RBP4 secretion is increased in the adipocytes of animals or humans with type 2 diabetes, obesity, and metabolic syndrome, but its role in preadipocyte differentiation remains unclear. In this study, we investigated the effect of RBP4 on the differentiation of porcine preadipocytes into adipocytes. The results suggest that RBP4 significantly suppresses the differentiation of porcine preadipocytes into adipocytes, including those treated with the hormone cocktail methylisobutylxanthine–dexamethasone–insulin. RBP4 also weakened the activity of normal threonine 308, the phosphorylation of serine/threonine kinase AKT, and downstream insulin signaling, including the mammalian target of rapamycin (mTOR) and β-catenin. Moreover, the activation of insulin signaling mediated by knockdown RBP4 in porcine preadipocytes was recovered in the suppression of LY294002. RBP4 also had a suppressive effect on the differentiation of porcine preadipocytes by decreasing the activation of insulin signaling pathways.

scholarly journals mTOR signaling mediates ILC3-driven immunopathology

2021 ◽  
Author(s):  
Claudia Teufel ◽  
Edit Horvath ◽  
Annick Peter ◽  
Caner Ercan ◽  
Salvatore Piscuoglio ◽  
...  
Keyword(s):  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Lymphoid Cells ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Cell Numbers ◽  
Mucosal Tissues ◽  
Ifn Γ

AbstractInnate lymphoid cells (ILCs) have a protective immune function at mucosal tissues but can also contribute to immunopathology. Previous work has shown that the serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1) is involved in generating protective ILC3 cytokine responses during bacterial infection. However, whether mTORC1 also regulates IFN-γ-mediated immunopathology has not been investigated. In addition, the role of mTORC2 in ILC3s is unknown. Using mice specifically defective for either mTORC1 or mTORC2 in ILC3s, we show that both mTOR complexes regulate the maintenance of ILC3s at steady state and pathological immune response during colitis. mTORC1 and to a lesser extend mTORC2 promote the proliferation of ILC3s in the small intestine. Upon activation, intestinal ILC3s produce less IFN-γ in the absence of mTOR signaling. During colitis, loss of both mTOR complexes in colonic ILC3s results in the reduced production of inflammatory mediators, recruitment of neutrophils and immunopathology. Similarly, treatment with rapamycin after colitis induction ameliorates the disease. Collectively, our data show a critical role for both mTOR complexes in controlling ILC3 cell numbers and ILC3-driven inflammation in the intestine.

scholarly journals SGK1, the New Player in the Game of Resistance: Chemo-Radio Molecular Target and Strategy for Inhibition

2016 ◽  
Vol 39 (5) ◽  
pp. 1863-1876 ◽  
Author(s):  
Cristina Talarico ◽  
Vincenzo Dattilo ◽  
Lucia D'Antona ◽  
Miranda Menniti ◽  
Cataldo Bianco ◽  
...  
Keyword(s):  
Hormonal Regulation ◽  
Cell Cycle Control ◽  
Selective Advantage ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Cancer Models ◽  
Control Regulation ◽  
Key Enzyme

The serum- and glucocorticoid-regulated kinase (SGK) family consists of three members, SGK1, SGK2 and SGK3, all displaying serine/threonine kinase activity and sharing structural and functional similarities with the AKT family of kinases. SGK1 was originally described as a key enzyme in the hormonal regulation of several ion channels and pumps. Over time, growing and impressive evidence has been accumulated, linking SGK1 to the cell survival, de-differentiation, cell cycle control, regulation of caspases, response to chemical, mechanical and oxidative injury in cancer models as well as to the control of mitotic stability. Much evidence shows that SGK1 is over-expressed in a variety of epithelial tumors. More recently, many contributions to the published literature demonstrate that SGK1 can mediate chemo-and radio-resistance during the treatment of various human tumors, both in vitro and in vivo. SGK1 appears therefore as a dirty player in the stress response to chemical and radio-agents, responsible of a selective advantage that favors the uncontrolled tumor progression and the selection of the most aggressive clones. The purpose of this review is the analysis of the literature describing SGK1 as central node of the cell resistance, and a summary of the possible strategies in the pharmacological targeting of SGK1.

scholarly journals A Ragulator–BORC interaction controls lysosome positioning in response to amino acid availability

2017 ◽  
Vol 216 (12) ◽  
pp. 4183-4197 ◽  
Author(s):  
Jing Pu ◽  
Tal Keren-Kaplan ◽  
Juan S. Bonifacino
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cellular Response ◽  
Mammalian Target Of Rapamycin ◽  
Small Gtpase ◽  
Regulatory Effect ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Amino Acid Availability ◽  
Amino Acid Depletion

Lysosomes play key roles in the cellular response to amino acid availability. Depletion of amino acids from the medium turns off a signaling pathway involving the Ragulator complex and the Rag guanosine triphosphatases (GTPases), causing release of the inactive mammalian target of rapamycin complex 1 (mTORC1) serine/threonine kinase from the lysosomal membrane. Decreased phosphorylation of mTORC1 substrates inhibits protein synthesis while activating autophagy. Amino acid depletion also causes clustering of lysosomes in the juxtanuclear area of the cell, but the mechanisms responsible for this phenomenon are poorly understood. Herein we show that Ragulator directly interacts with BLOC-1–related complex (BORC), a multi-subunit complex previously found to promote lysosome dispersal through coupling to the small GTPase Arl8 and the kinesins KIF1B and KIF5B. Interaction with Ragulator exerts a negative regulatory effect on BORC that is independent of mTORC1 activity. Amino acid depletion strengthens this interaction, explaining the redistribution of lysosomes to the juxtanuclear area. These findings thus demonstrate that amino acid availability controls lysosome positioning through Ragulator-dependent, but mTORC1-independent, modulation of BORC.

scholarly journals mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

2018 ◽  
Vol 19 (8) ◽  
pp. 2226 ◽  
Author(s):  
Larisa Ryskalin ◽  
Fiona Limanaqi ◽  
Alessandro Frati ◽  
Carla Busceti ◽  
Francesco Fornai
Keyword(s):  
Neurological Disorders ◽  
Drugs Of Abuse ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Neuropsychiatric Disorders ◽  
Environmental Cues ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Mtor Signalling

The mammalian target of rapamycin (mTOR) is an ubiquitously expressed serine-threonine kinase, which senses and integrates several intracellular and environmental cues to orchestrate major processes such as cell growth and metabolism. Altered mTOR signalling is associated with brain malformation and neurological disorders. Emerging evidence indicates that even subtle defects in the mTOR pathway may produce severe effects, which are evident as neurological and psychiatric disorders. On the other hand, administration of mTOR inhibitors may be beneficial for a variety of neuropsychiatric alterations encompassing neurodegeneration, brain tumors, brain ischemia, epilepsy, autism, mood disorders, drugs of abuse, and schizophrenia. mTOR has been widely implicated in synaptic plasticity and autophagy activation. This review addresses the role of mTOR-dependent autophagy dysfunction in a variety of neuropsychiatric disorders, to focus mainly on psychiatric syndromes including schizophrenia and drug addiction. For instance, amphetamines-induced addiction fairly overlaps with some neuropsychiatric disorders including neurodegeneration and schizophrenia. For this reason, in the present review, a special emphasis is placed on the role of mTOR on methamphetamine-induced brain alterations.

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