Modulation of GPR133 (ADGRD1) signaling by its intracellular interaction partner extended synaptotagmin 1
Year: 2024
Type: article
Abstract: GPR133 (ADGRD1) is an adhesion G-protein-coupled receptor that signals through Gαs/cyclic AMP (cAMP) and is required for the growth of glioblastoma (GBM), an aggressive brain malignancy. The regulation of GPR133 signaling is incompletely understood. Here, we use proximity biotinylation proteomics to identify ESYT1, a Ca 2+ -dependent mediator of endoplasmic reticulum-plasma membrane bridge formation, as an intracellular interactor of GPR133. ESYT1 knockdown or knockout increases GPR133 signaling, while its overexpression has the opposite effect, without altering GPR133 levels in the plasma membrane. The GPR133-ESYT1 interaction requires the Ca 2+ -sensing C2C domain of ESYT1. Thapsigargin-mediated increases in cytosolic Ca 2+ relieve signaling-suppressive effects of ESYT1 by promoting ESYT1-GPR133 dissociation. ESYT1 knockdown or knockout in GBM slows tumor growth, suggesting tumorigenic functions of ESYT1. Our findings demonstrate a mechanism for the modulation of GPR133 signaling by increased cytosolic Ca 2+ , which reduces the signaling-suppressive interaction between GPR133 and ESYT1 to raise cAMP levels.
Source: Cell Reports
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: California Department of Fish and Game, New York State Stem Cell Science, Broad Institute, Deutsche Forschungsgemeinschaft, National Institutes of Health, NYU Grossman School of Medicine, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: The role of GPR133 in glioblastoma, Identification and molecular characterization of FGFR4 p.G388R variant signaling in cerebellar hemangioblastomas, G2312702310, G2641952301, LTQ-Orbitrap Mass Spectrometer., Calcium dynamics and signaling in glioma, G4326892307, Fingerprinting-Based Neuronal Fiber Identification in Brain Surgery, G6367849451, G7344166158, G7874994702, Clinical and Translational Science Award, Cancer Center Support Grant, Developmentally Regulated Enhancers and Chromatin Architecture in Human Neurogenesis
OpenAlex ID: W4396946211