A spatially regulated GTPase cycle of Rheb controls growth factor signaling to mTORC1
| Autor: | Kraemer Au, Antonios D. Konitsiotis, Lisaweta Roßmannek, Corinna Klein, Angel Stanoev, Kovacevic M, Bastiaens Pih |
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| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
GTPase-activating protein biology Chemistry Growth factor medicine.medical_treatment GTPase mTORC1 Cell biology 03 medical and health sciences Cytosol 0302 clinical medicine medicine biology.protein Small GTPase 030217 neurology & neurosurgery PI3K/AKT/mTOR pathway 030304 developmental biology RHEB |
| DOI: | 10.1101/472241 |
| Popis: | Growth factors initiate anabolism by activating mechanistic target of rapamycin complex 1 (mTORC1) via the small GTPase Rheb. We show that the GTPase cycle of Rheb is spatially regulated by the interaction with its GDI-like solubilizing factor (GSF) – PDEδ. Arl2-GTP mediated localized release of cytosolic Rheb-GTP from PDEδ deposits it onto perinuclear membranes where it forms a complex with mTORC1. The membrane associated GTPase activating protein (GAP) TSC2 hydrolyzes Rheb-GTP, weakening the interaction with mTOR. Rheb-GDP is readily released into the cytosol where it is maintained soluble by interaction with PDEδ. This solubilized Rheb is re-activated by nucleotide exchange to be re-deposited by Arl2-mediated release onto perinuclear membranes. This spatial GTPase cycle thereby enables mTORC1 activation to be solely controlled by growth factor induced inactivation of TSC2. The coupling between mTOR activation and spatially regulated Rheb nucleotide exchange makes growth factor induced proliferation critically dependent on PDEδ expression. |
| Databáze: | OpenAIRE |
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