Max Planck Research Group Demetriades

Cell Growth Control in Health and Age-related Disease

Cell growth is a crucial and tightly regulated process. Cells uptake nutrients from their environment (such as amino acids, sugars, and lipids), and use them to synthesize various macromolecules, which they incorporate to increase their mass and grow. As growth is very energy consuming, cells have developed mechanisms to sense environmental conditions and to adjust their metabolism accordingly, so that they only grow when conditions are optimal.

These mechanisms are of great importance, as dysregulation of growth can lead to life-threatening disorders, such as cancer and other age-related diseases.

The mTOR kinase, as part of the mTOR complexes 1 (mTORC1) and 2 (mTORC2), is a master growth regulator. It functions as a sensor and a molecular rheostat that links the information from the cellular milieu to the growth properties of the cells. A large number of inputs converge on mTORC1 to regulate growth. Nutrients, energy, and growth factors activate this complex, whereas various stresses strongly inhibit its activity. Besides cell growth, mTOR activity affects the majority of cellular functions and can therefore influence organismal health, lifespan and ageing. Importantly, mutations on upstream pathway components, such as the inhibitory Tuberous Sclerosis Complex (TSC) proteins, can lead to mTOR hyperactivation, and, thus, are clinically relevant.

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Research Group Leader

Constantinos Demetriades, PhD

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Office 2-AW-050
Max Planck Institute for Biology of Ageing (MPI-AGE)
Joseph-Stelzmann Str. 9B
50931 Cologne, Germany

Cell Growth control in Health and age-related Disease
In cells lacking components of the TSC, mTOR demonstrates aberrant, constitutive lysosomal localization - and thus remains hyperactive - even under conditions of nutrient (amino acid) deprivation. Confocal microscopy images showing that mTOR (red) co-localizes with lysosomes (marked by LAMP2, blue) in TSC2-null cells (see upper right cell). Exogenous TSC2 expression (see lower left cell, marked by EGFP) restores mTOR localization, which becomes diffusely cytoplasmic.

Our work combines high-throughput Omics approaches (functional genomic screens, proteomic analyses), along with elegant molecular biology, biochemistry and high-resolution microscopy techniques. We make use of human, mouse and Drosophila cell lines, to identify evolutionarily conserved processes and to address multiple fundamental questions: How is cell growth regulated in normal cells? How does its dysregulation contribute to the development of age-related disease? How do cells sense the presence or absence of nutrients, to regulate growth? How is information from multiple diverse signals integrated to regulate TSC/mTOR? How are these protein complexes regulated in a spatiotemporal and tissue-specific manner?

Our research aims to elucidate existing and novel molecular mechanisms of cell growth control, mainly via regulation of the TSC and mTOR complexes, and to identify and functionally characterize novel components / regulators of these complexes, focusing on their putative implementation as new targets for drug development.

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Third-party funding

  • 2022 | Research Unit FOR2722 Grant
               German Research Foundation (DFG)
     
  • 2019 | Alexander von Humboldt Foundation
               Postdoctoral Humboldt-Bayer Research Fellowship to Dr. Yoav Elkis (2019-2022)
     
  • 2019 | Heineman Project Grant (2019-2022)
               Minna-James-Heineman Foundation
              
  • 2017 |  European Research Council Starting Grant (ERC-StG-2017)
                Amino acid sensing and mTOR signaling (2018-2023)