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Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion.
Bozadjieva N, Blandino-Rosano M, Chase J, Dai XQ, Cummings K, Gimeno J, Dean D, Powers AC, Gittes GK, Rüegg MA, Hall MN, MacDonald PE, Bernal-Mizrachi E
(2017) J Clin Invest 127: 4379-4393
MeSH Terms: Animals, Glucagon, Glucagon-Secreting Cells, Hepatocyte Nuclear Factor 3-beta, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Knockout, Regulatory-Associated Protein of mTOR, Signal Transduction
Show Abstract · Added September 21, 2018
Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, the mechanisms responsible for the regulation of pancreatic α cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of α cell mass and glucagon secretion. Using mice with tissue-specific deletion of the mTORC1 regulator Raptor in α cells (αRaptorKO), we showed that mTORC1 signaling is dispensable for α cell development, but essential for α cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in αRaptorKO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptorKO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in KATP channel subunit expression and activity. Additionally, our data identify the mTORC1/FoxA2 axis as a link between mTORC1 and transcriptional regulation of key genes responsible for α cell function. Thus, our results reveal a potential function of mTORC1 in nutrient-dependent regulation of glucagon secretion and identify a role for mTORC1 in controlling α cell-mass maintenance.
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1 Members
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9 MeSH Terms
Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways.
Wang S, Amato KR, Song W, Youngblood V, Lee K, Boothby M, Brantley-Sieders DM, Chen J
(2015) Mol Cell Biol 35: 1299-313
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins, Cell Proliferation, Cells, Cultured, Endothelial Cells, Gene Deletion, Human Umbilical Vein Endothelial Cells, Humans, Mechanistic Target of Rapamycin Complex 2, Mice, Multiprotein Complexes, Neovascularization, Physiologic, Phosphorylation, Protein Kinase C-alpha, Proto-Oncogene Proteins c-akt, Rapamycin-Insensitive Companion of mTOR Protein, Regulatory-Associated Protein of mTOR, Signal Transduction, TOR Serine-Threonine Kinases, Vascular Endothelial Growth Factor A
Show Abstract · Added February 15, 2016
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates a diverse array of cellular processes, including cell growth, survival, metabolism, and cytoskeleton dynamics. mTOR functions in two distinct complexes, mTORC1 and mTORC2, whose activities and substrate specificities are regulated by complex specific cofactors, including Raptor and Rictor, respectively. Little is known regarding the relative contribution of mTORC1 versus mTORC2 in vascular endothelial cells. Using mouse models of Raptor or Rictor gene targeting, we discovered that Rictor ablation inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation and assembly in vitro and angiogenesis in vivo, whereas the loss of Raptor had only a modest effect on endothelial cells (ECs). Mechanistically, the loss of Rictor reduced the phosphorylation of AKT, protein kinase Cα (PKCα), and NDRG1 without affecting the mTORC1 pathway. In contrast, the loss of Raptor increased the phosphorylation of AKT despite inhibiting the phosphorylation of S6K1, a direct target of mTORC1. Reconstitution of Rictor-null cells with myristoylated AKT (Myr-AKT) rescued vascular assembly in Rictor-deficient endothelial cells, whereas PKCα rescued proliferation defects. Furthermore, tumor neovascularization in vivo was significantly decreased upon EC-specific Rictor deletion in mice. These data indicate that mTORC2 is a critical signaling node required for VEGF-mediated angiogenesis through the regulation of AKT and PKCα in vascular endothelial cells.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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1 Members
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21 MeSH Terms
The targeted podocyte.
Fogo AB
(2011) J Clin Invest 121: 2142-5
MeSH Terms: Adaptor Proteins, Signal Transducing, Adult, Animals, Carrier Proteins, Child, Diabetic Nephropathies, Disease Models, Animal, Genetic Predisposition to Disease, Humans, Kidney Glomerulus, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Multiprotein Complexes, Podocytes, Proteins, Rapamycin-Insensitive Companion of mTOR Protein, Regulatory-Associated Protein of mTOR, Sirolimus, TOR Serine-Threonine Kinases, Trans-Activators, Transcription Factors
Show Abstract · Added January 20, 2012
The podocyte plays a key role both in maintenance of the glomerular filtration barrier and in glomerular structural integrity. Podocyte injury and loss contribute to proteinuria and progressive sclerosis. Inhibitors of mammalian target of rapamycin (mTOR) have variably decreased or caused proteinuria and sclerosis in human disease and experimental settings. In this issue of the JCI, two interesting studies of podocyte-specific manipulation of the mTOR system shed light on the complexity of this pathway in the podocyte.
2 Communities
1 Members
0 Resources
22 MeSH Terms