Metabolic fine tuning
Amino acids as signaling molecules: Interaction uncovered
Amino acids are important signaling molecules which influence cellular and organismal metabolism, however, their molecular targets are not yet completely identified. A systems study has now shed light into the molecular interaction network and the diverse cellular functions of amino acids.
Amino acids are recognized as essential building blocks for proteins and are abundant in nutrient rich environments. In addition, amino acids are also important signaling molecules which influence cellular and organismal metabolism and the malignancy of cancer cells. The oncogenic protein kinase mTOR (mammalian target of rapamycin) is a key player in the cellular signaling network which transduces amino acid signals and promotes cell growth.
Do amino acids also target other signaling proteins to fine-tune cellular metabolism? This question is central to the project of e:Med scientists around Professor Kathrin Thedieck, Dr. Sascha Schäuble and Dr. Daryl Shanley (MAPTor-NET and GlioPATH research alliances).The scientists conducted a systems study in which they combined lab experiments with dynamic in silico modeling of the amino acid signaling network, as well as proteomics with text-mining analyses.
They found that next to the well-known amino acid target mTOR also other signaling molecules - class I phosphatidylinositide kinases (PI3K) and the energy-sensing kinase AMPK (AMP-dependent kinase) - are activated by amino acids. Thus, the influence of amino acids is broader than previously assumed. One of the targets, AMPK, is widely considered as an mTOR antagonist as the two kinases have opposite roles in autophagy regulation. Here, the authors found that mTOR and AMPK are concomitantly active when amino acids are present, allowing active autophagy and protein synthesis at the same time. Autophagy is a cellular process in which macromolecules are degraded. Autophagy is therefore not only important for the clearance of damaged cellular components, but it also provides metabolite intermediates required for biosynthetic processes, including translation and cellular growth.
The study of Dalle Pezze et al. broadens the scope of the cellular functions of amino acids and shows how to decode complex signaling networks by combined modeling and lab experiments.
Publication:
Dalle Pezze, P., Ruf, S., Sonntag, A.G., Langelaar-Makkinje, M., Hall, P., Heberle, A.M., Navas, P.R., van Eunen, K., Tölle, R.C., Schwarz, J.J., Wiese, H., Warscheid, B., Deitersen, J., Stork, B., Fäßler, E., Schäuble, S., Hahn, U., Horvatovich, P., Shanley, D.P., Thedieck, K., 2016. A systems study reveals concurrent activation of AMPK and mTOR by amino acids. Nat Commun 7, 13254. doi.org/10.1038/ncomms13254
Contact:
Prof. Kathrin Thedieck, MAPTorNet and GlioPATH
Lab for Metabolic Signaling
Carl von Ossietzky University Oldenburg