A novel mechanism protects against cancer cell migration and neuron hyperexcitability

G3BP proteins inhibit the metabolic driver MTOR, a signaling protein that plays a central role in tumor diseases and developmental disorders of the brain. This is reported this week in the journal Cell by scientists of the BMBF-funded e:Med junior network GlioPATH together with a Europe-wide research network. G3BP proteins may serve as molecular markers to personalize therapies.

The signaling protein MTOR (Mechanistic Target of Rapamycin) is a sensor for nutrients such as amino acids and sugars. When sufficient nutrients are available, MTOR boosts metabolism and ensures that sufficient energy and building blocks are available for the growth and function of all cells in the human body. "Because MTOR is such a central switch for metabolism, errors in its activation lead to serious diseases. These include cancers associated with excessive metabolic activity, cell growth and proliferation. Dysregulated MTOR also causes malformations of the nervous system, disturbing stimulus processing and eliciting behavioral disorders and epilepsy" explains the biochemist Kathrin Thedieck.

To prevent errors in MTOR-based signal processing, the cell controls its activity very precisely. This is achieved through suppressors, molecules that inhibit a protein and help to regulate its activity. The TSC complex is such a suppressor for MTOR. It is named after the disease that is caused by its absence - tuberous sclerosis complex (TSC) disease. Together with MTOR, the TSC complex localizes to small cellular structures, the lysosomes, where it keeps MTOR in check. If the TSC complex - for example due to changes (mutations) in one of its components - no longer remains at the lysosome, this can lead to excessive MTOR activity with severe consequences for human health. Until now, it was not clear how the TSC complex is anchored to lysosomes and which other proteins are involved in this regulation.

A molecular TSC anchor at lysosomes

Together with many other colleagues, the GlioPATH scientists Kathrin Thedieck, Christiane Opitz, Saskia Trump and Ines Heiland investigated how the TSC complex binds to lysosomes. They discovered that the G3BP (Ras GTPase-activating protein-binding protein) proteins localize to lysosomes, together with the TSC complex. There, the G3BP proteins form an anchor that ensures that the TSC complex can bind to the lysosomes. “Phylogenetically, the G3BPs appeared together with the TSC complex, underlining their joint function”, says the systems biologist Ines Heiland. The G3BPs’ anchor function plays a crucial role in breast cancer. If the amount of G3BP decreases, not only MTOR activity but also cell motility is increased in cancer cell cultures. MTOR inhibitors suppress this hypermotility. In breast cancer patients, low G3BP correlates with a worse prognosis. “G3BP proteins could therefore be valuable markers to personalize therapies and improve the efficacy of drugs that inhibit MTOR”, says the chemist Saskia Trump.

G3BP proteins also inhibit MTOR in the brain. In zebrafish, an important animal model for pharmaceutical research, the scientists observed disturbances in brain development when G3BP was missing. Loss of G3BP also resulted in neuronal hyperactivity and ensuing behavioral abnormalities reminiscent of epilepsy in humans. Compounds that target MTOR suppressed the neuronal hyperactivity. "We therefore anticipate that patients with neurological disorders and G3BP malfunction could benefit from MTOR inhibitors and we look forward to further exploring this together with our scientific network," says the physician and molecular cell biologist Christiane Opitz.

Original publication:

Prentzell, M. T., Rehbein, U., Cadena Sandoval, M., De Meulemeester, A.-S., Baumeister, R., Brohée, L., Berdel, B., Bockwoldt, M., Carroll, B., Chowdhury, S. R., von Deimling, A., Demetriades, C., Figlia, G., de Araujo, M. E. G., Heberle, A. M., Heiland, I., Holzwarth, B., Huber, L. A., Jaworski, J., Kedra, M., Kern, K., Kopach, A., Korolchuk, V. I., van 't Land-Kuper, I., Macias, M., Nellist, M., Palm, W., Pusch, S., Ramos Pittol, J. M., Reil, M., Reintjes, A., Reuter, F., Sampson, J. R., Scheldeman, C., Siekierska, A., Stefan, E., Teleman, A. A., Thomas, L. E., Torres-Quesada, O., Trump, S., West, H. D., de Witte, P., Woltering, S., Yordanov, T. E., Zmorzynska, J., Opitz, C. A. and Thedieck, K. (2021). "G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling." Cell. doi.org/10.1016/j.cell.2020.12.024.

GlioPATH Consortium:

Dr. Christiane Opitz
Brain Cancer Metabolism
German Research Cancer Center, DKFZ, Heidelberg

Prof. Dr. Kathrin Thedieck
Lab for Metabolic Signaling
Institut für Biochemie, University Innsbruck, Austria
Department für Neurowissenschaften, Universität Oldenburg, Deutschland
Department of Pediatrics, University of Groningen, University Medical Center Groningen, Niederlande

Dr. Saskia Trump
Research Group Molecular Epidemiology
Charité - Universitätsmedizin Berlin and Berlin Institute of Health, BIH, Berlin
formerly Helmholtz Center for Environmental Research - UFZ, Leipzig

Prof. Dr. Ines Heiland
Molecular Biology and Bioinformatics
Dept. of Arctic and Marine Biology
Faculty of Bioscience, Fisheries and Economics
UiT The Arctic University of Norway, Tromso, Norway