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. 2015;14(16):2571-7.
doi: 10.1080/15384101.2015.1056947.

Cellular adaptation to nutrient deprivation: crosstalk between the mTORC1 and eIF2α signaling pathways and implications for autophagy

Jordan C Wengrod  1 , Lawrence B Gardner
Affiliations

Cellular adaptation to nutrient deprivation: crosstalk between the mTORC1 and eIF2α signaling pathways and implications for autophagy

Jordan C Wengrod et al. Cell Cycle. 2015.

Abstract

The hostile tumor microenvironment results in the generation of intracellular stresses including hypoxia and nutrient deprivation. In order to adapt to such conditions, the cell utilizes several stress-response mechanisms, including the attenuation of protein synthesis, the inhibition of cellular proliferation, and induction of autophagy. Autophagy leads to the degradation of cellular contents, including damaged organelles and mutant proteins, which the cell can then use as an alternate energy source. Two integral changes to the signaling milieu to promote such a response include inhibition of the mammalian target of rapamycin complex 1 (mTORC1) and phosphorylation of eIF2α. This review will describe how conditions found in the tumor microenvironment regulate mTORC1 as well as eIF2α, the downstream impact of these modifications, and the implications in tumorigenesis. We will then discuss the remarkable similarities and overlapping function of these 2 signaling pathways, focusing on the response to amino acid deprivation, and present a new model involving crosstalk between them based on our recent work.

Keywords: PP6C; autophagy; eIF2α; integrated stress response; mTORC1; unfolded protein response.

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Figures

Figure 1.
Figure 1.
mTORC1 signaling pathway. mTORC1 is a serine/theronine kinase complex that receives information regarding the nutrient status of the cell and orchestrates a pro-survival response to the conditions in the tumor microenvironment. In response to low glucose levels, intracellular AMP concentrations increase, leading to the activation of AMPK, which negatively regulates mTORC1 through activation of the TSC complex. In response to amino acid deprivation, the Rag-GTPases are unable to associate with mTORC1, preventing its activation. mTORC1 inhibition limits cellular energy use by regulating cell size and proliferation through S6K and 4EBP1, respectively. Additionally, mTORC1 inhibition induces autophagy to produce an alternative energy source.
Figure 2.
Figure 2.
The integrated stress response. eIF2α is phosphorylated by kinases that are activated in response to particular stresses. Amino acid deprivation activates GCN2, accumulated proteins in the ER activates PERK, single stranded RNA viruses activate PKR, and low heme concentrations activate HRI. Phosphorylated eIF2α leads to a decrease in cap-dependent protein synthesis and increases the transcripts containing upstream open reading frames (uORFS) such as the stress responsive transcription factor ATF4. Phosphorylated eIF2α has also been in inducing autophagy in response to amino acid deprivation.
Figure 3.
Figure 3.
Canonical and non-canonical mTORC1-mediated regulation of autophagy. Under periods of nutrient deprivation, mTORC1 inhibition enables the formation of the ULK1/ATG13 scaffold complex, which allows for the initial nucleation steps of autophagy to occur. mTORC1 inhibition also activates the phosphatase PP6C. PP6C then associates with GCN2 in a complex with a PP6 regulatory protein, promoting its dephosphorylation and activation. Activated GCN2 then leads to the phosphorylation of eIF2α and induction of autophagy.
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