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CORDIS

The stress granule machinery controls metabolic signalling through mTOR at steady-state

Project description

Stress granule machinery controls metabolic signalling

Mammalian/ mechanistic target of rapamycin (mTOR) kinase regulates cell growth, survival and death via a complex signalling network. Aberrant mTOR signalling is implicated in cancer, disturbed immunity, insulin resistance, and other age-related conditions. Recent data show that core stress granule (SG) proteins bind mTOR in the absence of stress granules and control mTOR activity in response to growth factor signals and nutrients. The EU-funded BEYOND STRESS project will employ a combination of modern technologies to investigate the role of SG proteins in mTOR regulation by metabolic cues and the interplay with stress signals. The project will also explore the linkage of SG proteins with prognosis, drug response and outcome in breast cancer.

Objective

mTOR kinase is an oncogenic master regulator of metabolism and cell growth and is known to reside in two multiprotein complexes. Upon stress, mTOR is inhibited by stress granules (SGs), which recruit mRNAs and signaling factors to promote survival. Current work largely addresses the functions of SG proteins under stress, focusing on their RNA binding properties and SG assembly. However, non-stress functions are emerging. I propose that SG proteins have prime functions in mTOR signaling at metabolic steady-state, in the absence of SGs. Our preliminary data show that core SG proteins bind mTOR at steady-state and suggest that they are key controllers of mTOR.

In BEYOND STRESS, we will investigate SG proteins as a novel class of mTOR regulators at steady-state.

By means of deep proteomics, proteo-metabo-flux, RNASeq, systems modelling, mechanistic and cell bio-logical studies, we will identify and functionally characterize the SG interactome of the mTOR complexes. We will delineate the steady-state inputs that signal through SG proteins to mTOR, and we will unravel the mechanistic interplay through which SG assembly impinges on metabolic signaling upon stress. As levels of core SG proteins correlate with cancer outcome, we will explore their linkage with metabolic signaling, prognosis and drug response in breast cancer.

BEYOND STRESS is ground-breaking as
(i) it links SG protein research in stress to steady-state mTOR signaling;
(ii) a unifying paradigm of mTOR regulation at steady-state and stress will open new horizons for research on metabolic signaling; and
(iii) SG proteins are emerging as markers and targets for oncogenic signaling through mTOR.
While focusing on mTOR and breast cancer, BEYOND STRESS will likely translate to further networks and tumor entities, opening new avenues to signaling and cancer research.

Host institution

UNIVERSITAETSKLINIKUM ESSEN
Net EU contribution
€ 2 156 131,74
Address
HUFELANDSTRASSE 55
45147 Essen
Germany

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Region
Nordrhein-Westfalen Düsseldorf Essen, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 2 156 131,74

Beneficiaries (2)