mTOR - a central regulator of cell metabolism

Wed, 04/29/2015 - 15:05

The mammalian target of rapamycin (mTOR) signaling pathway allows cells to monitor environmental signals like nutrient availability and oxygen levels. mTOR is a phosphoinositide 3-kinase (PI3K)-related protein that assembles into large protein complexes (mTORC1 and mTORC2) capable of regulating cell metabolism, growth, and proliferation. mTOR complexes can be stimulated by extracellular growth factors such through the insulin and Ras signaling pathways as well as by intracellular signals such as the ratio of ATP:ADP within the cell or by amino acid levels. The tuberous sclerosis complex (TSC) is an important sensor module that integrates many of these signals and activates or inhibits mTOR accordingly. TSC acts as a GTPase-activating protein (GAP) for Rheb (Ras homolog enriched in brain), a direct interactor of the mTOR complex. GTP bound Rheb stimulates mTOR activity. However TSC negatively regulates mTOR activity by converting GTP bound Rheb to the GDP bound state. mTOR responds to these signals through the phosphorylation of downstream effectors. For example, mTOR can positively regulate protein synthesis by phosphorylating and inactivating a translational repressor. mTOR also responds to nutrient availability by activating or repressing autophagy, a cellular process by which organelles and macromolecules are degraded to provide material for energy production and protein synthesis. mTOR is often deregulated in cancer, diabetes, and obesity making it an important target for drug design and for understanding complex diseases.

Gao et al. used the mTOR antibody to monitor expression levels in uterine cells in response to the changing hormone levels of pregnant sheep (1). Additionally they used a phospho-specific version of the mTOR antibody to show mTOR localization changes from the cytoplasm to the nucleus upon modification. The Sarbossov group at the M.D. Anderson cancer center examined the subcellular localization of specific mTOR complexes (2). They used the mTOR antibody for immunostaining in combination with Rictor, a marker protein specific to mTORC2. Using this strategy they showed mTORC2 is primarily associated with the endoplasmic reticulum. A group of Italian researchers studying the role of inflammation responses in astrocytes found mTOR is an important regulator of nitric oxide levels (3). They performed western blots with the phospho-specific mTOR antibody to monitor mTOR activation in response to pro-inflammatory cytokines. These experiments allowed the group to demonstrate mTOR activity regulates the mRNA stability of a nitric oxide producing enzyme. The same group examined soluble factors secreted by glioma cells and the effect they have on neighboring microglial cells (4). They monitored microglial cells after exposure to conditioned media from basal glioma cells as well as media from glioma cells induced with inflammatory factors. Cellular responses were examined using the phospho-specific mTOR antibody. These experiments showed differences in mTOR activation as well as its downstream targets depending on the different glioma secreted factors.

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  1. 19299312
  2. 21867682
  3. 21208419
  4. 24689533

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