Role of mTor signaling for tubular function and disease

Physiology ◽  
2021 ◽  
Author(s):  
Florian Grahammer ◽  
Tobias B Huber ◽  
Ferruh Artunc
Keyword(s):  
Diabetic Nephropathy ◽  
Actin Cytoskeleton ◽  
Mtor Signaling ◽  
Tubular Function ◽  
Target Of Rapamycin ◽  
Multiprotein Complexes ◽  
Mechanistic Target Of Rapamycin ◽  
Transport Regulation ◽  
Disease Entities

The mechanistic target of rapamycin (mTOR) forms two distinct intracellular multiprotein complexes that control a multitude of intracellular processes linked to metabolism, proliferation, actin cytoskeleton and survival. Recent studies have identified the importance of these complexes for transport regulation of ions and nutrients along the entire nephron. First reports could link altered activity of these complexes to certain disease entities i.e. diabetic nephropathy, AKI or hyperkalemia.

scholarly journals Regulation of protein kinase Cδ Nuclear Import and Apoptosis by Mechanistic Target of Rapamycin Complex-1

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Antonio Layoun ◽  
Alexander A. Goldberg ◽  
Ayesha Baig ◽  
Mikaela Eng ◽  
Ortal Attias ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nuclear Import ◽  
Target Of Rapamycin ◽  
Interferon Β ◽  
Structural Mechanism ◽  
Mechanistic Target Of Rapamycin ◽  
Kinase C ◽  
Nuclear Content ◽  
In Cells

AbstractInactivation of the protein complex ‘mechanistic target of rapamycin complex 1’ (mTORC1) can increase the nuclear content of transcriptional regulators of metabolism and apoptosis. Previous studies established that nuclear import of signal transducer and activator of transcription-1 (STAT1) requires the mTORC1-associated adaptor karyopherin-α1 (KPNA1) when mTORC1 activity is reduced. However, the role of other mTORC1-interacting proteins in the complex, including ‘protein kinase C delta’ (PKCδ), have not been well characterized. In this study, we demonstrate that PKCδ, a STAT1 kinase, contains a functional ‘target of rapamycin signaling’ (TOS) motif that directs its interaction with mTORC1. Depletion of KPNA1 by RNAi prevented the nuclear import of PKCδ in cells exposed to the mTORC1 inhibitor rapamycin or amino acid restriction. Mutation of the TOS motif in PKCδ led to its loss of regulation by mTORC1 or karyopherin-α1, resulting in increased constitutive nuclear content. In cells expressing wild-type PKCδ, STAT1 activity and apoptosis were increased by rapamycin or interferon-β. Those expressing the PKCδ TOS mutant exhibited increased STAT1 activity and apoptosis; further enhancement by rapamycin or interferon-β, however, was lost. Therefore, the TOS motif in PKCδ is a novel structural mechanism by which mTORC1 prevents PKCδ and STAT1 nuclear import, and apoptosis.

scholarly journals Mechanistic Target of Rapamycin Complex 2 Regulation of the Primary Human Trophoblast Cell Transcriptome

2021 ◽  
Vol 9 ◽  
Author(s):  
Fredrick J. Rosario ◽  
Amy Catherine Kelly ◽  
Madhulika B. Gupta ◽  
Theresa L. Powell ◽  
Laura Cox ◽  
...  
Keyword(s):  
Protein Expression ◽  
Gene Array ◽  
Target Of Rapamycin ◽  
Human Trophoblast ◽  
Mechanistic Target Of Rapamycin ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Cell Transcriptome ◽  
Pathway Analyses

Mechanistic Target of Rapamycin Complex 2 (mTORC2) regulates placental amino acid and folate transport. However, the role of mTORC2 in modulating other placental functions is largely unexplored. We used a gene array following the silencing of rictor to identify genes regulated by mTORC2 in primary human trophoblast (PHT) cells. Four hundred and nine genes were differentially expressed; 102 genes were down-regulated and 307 up-regulated. Pathway analyses demonstrated that inhibition of mTORC2 resulted in increased expression of genes encoding for pro-inflammatory IL-6, VEGF-A, leptin, and inflammatory signaling (SAPK/JNK). Furthermore, down-regulated genes were functionally enriched in genes involved in angiogenesis (Osteopontin) and multivitamin transport (SLC5A6). In addition, the protein expression of leptin, VEGFA, IL-6 was increased and negatively correlated to mTORC2 signaling in human placentas collected from pregnancies complicated by intrauterine growth restriction (IUGR). In contrast, the protein expression of Osteopontin and SLC5A6 was decreased and positively correlated to mTORC2 signaling in human IUGR placentas. In conclusion, mTORC2 signaling regulates trophoblast expression of genes involved in inflammation, micronutrient transport, and angiogenesis, representing novel links between mTOR signaling and multiple placental functions necessary for fetal growth and development.

scholarly journals Mechanistic target of rapamycin signaling in mouse models of accelerated aging

2019 ◽  
Vol 75 (1) ◽  
pp. 64-72 ◽  
Author(s):  
Jin Young Lee ◽  
Brian K Kennedy ◽  
Chen-Yu Liao
Keyword(s):  
Mouse Models ◽  
Accelerated Aging ◽  
Nutrient Sensing ◽  
Mtor Signaling ◽  
Human Diseases ◽  
Target Of Rapamycin ◽  
Cellular Processes ◽  
Positive Effects ◽  
Mechanistic Target Of Rapamycin ◽  
Age Related

Abstract The mechanistic target of rapamycin (mTOR) is an essential nutrient-sensing kinase that integrates and regulates a number of fundamental cellular processes required for cell growth, cell motility, translation, metabolism, and autophagy. mTOR signaling has been implicated in the progression of many human diseases, and its dysregulation has been reported in several pathological processes, especially in age-related human diseases and mouse models of accelerated aging. In addition, many studies have demonstrated that the regulation of mTOR activity has a beneficial effect on longevity in several mouse models of aging. However, not all mouse models of accelerated aging show positive effects on aging-associated phenotypes in response to targeting mTOR signaling. Here, we review the effects of interventions that modulate mTOR signaling on aging-related phenotypes in different mouse models of accelerated aging and discuss their implications with respect to aging and aging-related disorders.

Mechanistic target of rapamycin (MTOR) signaling during ovulation in mice

2014 ◽  
Vol 81 (7) ◽  
pp. 655-665 ◽  
Author(s):  
Dayananda Siddappa ◽  
Anitha Kalaiselvanraja ◽  
Vilceu Bordignon ◽  
Lisa Dupuis ◽  
Bernardo G. Gasperin ◽  
...  
Keyword(s):  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
Mechanistic Target Of Rapamycin
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