The Department of Biomedicine

BBB webinar: Kathrin Thedieck

Stress granule proteins meet TSC-mTOR signaling: an unexpected mechanism of lysosomal TSC tethering

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Kathrin Thedieck
Institute of Biochemistry, University of Innsbruck, Innsbruck, Austria

The tuberous sclerosis protein (TSC) complex acts as a tumor suppressor by restricting signaling through the metabolic master regulator mTORC1 (mechanistic target of rapamycin complex 1). Mutations in the TSC1 or TSC2 genes frequently occur in cancer and hereditary TSC disorder, characterized by tumor formation in multiple organs. The TSC complex senses anabolic signals, and suppresses pro-tumorigenic processes by inhibiting mTORC1 at its central signaling platform – the lysosomes. We conducted a detailed biochemical and cell biological study of a novel mechanism that drives breast cancer cell migration. We report that G3BP1 and G3BP2 (Ras GTPase-activating protein-binding proteins, G3BPs) act in a non-redundant manner to anchor the TSC complex to lysosomes and suppress activation of mTORC1 by nutritional signals. Like the TSC complex, deficiency of G3BP1 elicits phenotypes related to mTORC1 hyperactivity in the context of breast cancer and neuronal dysfunction. G3BP1 prevents mTORC1-driven cancer cell motility, and in agreement, low G3BP1 expression correlates with poor outcome in metastatic breast cancer. G3BP1 levels in cancer may therefore serve as predictors of clinical outcome and response to mTORC1 inhibitors.

Selected reference:

Prentzell MT, Rehbein U, Cadena Sandoval M et al. G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling. Cell, 2021,184:655-74

Chairperson: Mathias Ziegler, Department of Biomedicine