Amino acids stimulate phosphorylation of p70<sup> <i>S6k</i> </sup> and  organization of rat adipocytes into multicellular clusters

Fox, Heather L.; Kimball, Scot R.; Jefferson, Leonard S.; Lynch, Christopher J.

doi:10.1152/ajpcell.1998.274.1.c206

Cited by 123 publications

(96 citation statements)

References 39 publications

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“…[21][22][23]44 Our current data, thus far, clearly pointed to an interrelationship between activation of mTORC1 pathway and upregulation of LAT2 in the glomeruli of rats at 2 days after the induction of CGN before histological signs of crescent formation. However, whether upregulation of LAT2 itself could lead mTORC1 activation was not clear because there has been very few data showing that existence of amino acid transporter on the plasma membrane itself could function as a direct entrance that activates mTORC1 cascade.…”

Section: Activation Of Mtorc1 In Cells Expressing Lat2supporting

confidence: 66%

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Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

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Molecular mechanisms and signaling pathways leading to cellular proliferation and lesion formation in the crescentic glomerulonephritis (CGN) remain elusive. In the present study we have explored a potential role of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway and amino acid transporter (LAT) in the pathogenesis of CGN. Immunohistochemistry and western blot analysis of glomeruli isolated from a rat model of CGN revealed that activation of mTORC1 preceded crescent formation in glomerular parietal epithelial cells (PECs) and podocytes. Daily treatment of rats with the mTOR inhibitor everolimus just after induction of CGN was not beneficial and instead led to increased cellular necrosis of PECs. However, daily treatment starting 7 days after the onset of CGN was beneficial and maintained intact glomeruli. Out of three forms of L-type neutral amino acid transporters (LAT1-LAT3) studied here, only LAT2 was found to be upregulated in the PECs and podocytes in advance of the crescent formation as well as in the crescent lesion itself. Cell culture study revealed that plasma membrane expression of LAT2 markedly stimulated mTORC1 signaling pathway, which was significantly abrogated by coexistence of LAT inhibitor. Finally, LAT inhibitor significantly abrogated development of crescent formation of CGN on day 7. Our data suggest that LAT2 may have a pivotal role in the pathogenesis of CGN by activating the mTORC1 pathway in the glomerular epithelial cells. Crescentic glomerulonephritis (CGN) is the most severe form of glomerulonephritis, and if untreated, progresses to endstage renal failure within days or weeks of diagnosis. Despite different etiologies and clinical manifestations among patients with CGN, there is a common glomerular pathology characterized by the disruption of glomerular basement membrane (GBM), followed by the flow of plasma proteins and inflammatory cells into the Bowman's space. 1 Several studies suggest that proliferating glomerular epithelial cells and accumulation of infiltrated macrophages are the main components of the cellular crescents. 2-6 Recent reports have further revealed that the cellular crescent lesions in CGN consist of podocytes in addition to glomerular parietal epithelial cells (PECs) and macrophages. [7][8][9] It is increasingly evident that proinflammatory cytokines and growth hormones released by proliferating cells in the glomerulus are involved in the pathogenesis of crescent formation. [10][11][12][13] These factors stimulate the p38 mitogen-activated protein kinase (MAPK) pathway, resulting in the production of inflammatory mediators. [14][15][16] The involvement of the MAPK pathway in the pathogenesis of CGN was first reported by Bokemeyer et al, 17 who demonstrated a rapid and sustained activation of extracellular signal-regulated kinase in the glomeruli isolated from rat model of anti-GBM nephritis. A further study demonstrated that both podocytes and the crescent lesion are the main source of p38MAPK activation, although additional signaling path...

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Section: Activation Of Mtorc1 In Cells Expressing Lat2supporting

confidence: 66%

“…46,47 It is increasingly evident that elevation in the intracellular levels of BCAAs stimulates phosphorylation of these molecules, whereas deprivation of such amino acids promotes dephosphorylation of them. 21,23,44 However, mechanisms by which mTORC1 can sense changes in the levels of amino acids remain largely elusive.…”

Section: Discussionmentioning

confidence: 99%

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

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“…In mammalian cells, amino acid deprivation leads to decreased mTOR signaling and to decreased rates of protein synthesis, effects that are rapidly reversed by readdition of amino acids (30,46). Among the amino acids, changes in leucine levels alone are sufficient to regulate the phosphorylation state and activity of the mTOR pathway (46,69).…”

Section: Mtor and Amino Acid Availabilitymentioning

confidence: 99%

Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals

Miyazaki

Esser²

2009

Journal of Applied Physiology

166

142

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Miyazaki M, Esser KA. Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals. J Appl Physiol 106: 1367-1373, 2009; doi:10.1152/japplphysiol.91355.2008.-Growth and maintenance of skeletal muscle mass is critical for long-term health and quality of life. Skeletal muscle is a highly adaptable tissue with well-known sensitivities to environmental cues such as growth factors, cytokines, nutrients, and mechanical loading. All of these factors act at the level of the cell and signal through pathways that lead to changes in phenotype through multiple mechanisms. In this review, we discuss the animal and cell culture models used and the signaling mechanisms identified in understanding regulation of protein synthesis in response to mechanical loading/resistance exercise. Particular emphasis has been placed on 1) alterations in mechanical loading and regulation of protein synthesis in both in vivo animal studies and in vitro cell culture studies and 2) upstream mediators regulating mammalian target of rapamycin signaling and protein synthesis during skeletal muscle hypertrophy. mechanical stretch; REDD2; overload; IGF-1; amino acids IT IS WIDELY ACCEPTED that repeated bouts of resistance exercise/ high-force contractions produce compensatory growth of skeletal muscle (35,42,47,95). The increase in skeletal muscle mass results from rates of protein synthesis increased more than changes in protein degradation with the net result being an accumulation of protein and increased fiber area (66,96). While the effect of resistance exercise/contraction on muscle mass has long been recognized, the mechanisms underlying the link between high resistance contractions and muscle growth are, to date, not fully understood.One of the important variables contributing to the growth response in skeletal muscle is the application of mechanical loading. For this review we use mechanical loading very generally as the application of force on the muscle or muscle cell. This force on the muscle can occur via active cross-bridge interactions (such as during concentric, isometric, or eccentric contractions) in a gravity-based environment or via external application of force such as passive stretching. The most established animal model for studying skeletal muscle hypertrophy in response to mechanical loading was described by Dr. A. L. Goldberg (38) and was referred to as work-induced muscle growth. This model is now commonly known as the synergist ablation/mechanical overload model and is a surgical model that involves cutting of the tendon and removal of the gastrocnemius muscle, resulting in loading and compensatory growth of the remaining plantar flexors, the plantaris, and soleus muscles. These muscles are involved in maintenance of posture and walking so are loaded by the body weight of the animal. Muscle mass changes are fairly rapid and the growth is robust, ranging from 40 to 200% depending on the muscle and species studied (7,37,38,53,56). Many labs use this model in their research programs to study mole...

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“…In particular, amino acids have been shown to activate an mTOR-dependent pathway that leads to the phosphorylation of two downstream effectors, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal S6 kinase 1 (S6K1) (15)(16)(17)(18). In adipocytes, mTOR is thought to regulate protein synthesis (19), adipose tissue morphogenesis (20), and leptin synthesis/secretion (21).…”

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confidence: 99%

Regulation of Peroxisome Proliferator–Activated Receptor-γ Activity by Mammalian Target of Rapamycin and Amino Acids in Adipogenesis

2004

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Adipocyte differentiation is a developmental process that is critical for metabolic homeostasis and nutrient signaling. The mammalian target of rapamycin (mTOR) mediates nutrient signaling to regulate cell growth, proliferation, and diverse cellular differentiation. It has been reported that rapamycin, the inhibitor of mTOR and an immunosuppressant, blocks adipocyte differentiation, but the mechanism underlying this phenomenon remains unknown. Here we show that mTOR plays a critical role in 3T3-L1 preadipocyte differentiation and that mTOR kinase activity is required for this process.

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Amino acids stimulate phosphorylation of p70^S6k and organization of rat adipocytes into multicellular clusters

Cited by 123 publications

References 39 publications

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals

Regulation of Peroxisome Proliferator–Activated Receptor-γ Activity by Mammalian Target of Rapamycin and Amino Acids in Adipogenesis

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Amino acids stimulate phosphorylation of p70 S6k and organization of rat adipocytes into multicellular clusters

Cited by 123 publications

References 39 publications

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals

Regulation of Peroxisome Proliferator–Activated Receptor-γ Activity by Mammalian Target of Rapamycin and Amino Acids in Adipogenesis

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Amino acids stimulate phosphorylation of p70^S6k and organization of rat adipocytes into multicellular clusters