ArticleCellular and molecular life sciences : CMLS2020
GPR50-Ctail cleavage and nuclear translocation: a new signal transduction mode for G protein-coupled receptors.
Article in Cellular and molecular life sciences : CMLS, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 17 citations in OpenAlex.
- Orphan GPR50 Restrains Neurite Outgrowth and Cell Migration by Activating the GJournal of pineal research · 2025Article
- Integrated Transcriptomic and Proteomic Study of the Mechanism of Action of the Novel Small-Molecule Positive Allosteric Modulator 1 in Targeting PAC1-R for the Treatment of D-Gal-Induced Aging Mice.International journal of molecular sciences · 2024Article
- Melatonin Offers Dual-Phase Protection to Brain Vessel Endothelial Cells in Prolonged Cerebral Ischemia-Recanalization Through Ameliorating ER Stress and Resolving Refractory Stress Granule.Translational stroke research · 2023Article
- The Orphan GPR50 Receptor Regulates the Aggressiveness of Breast Cancer Stem-like Cells via Targeting the NF-kB Signaling Pathway.International journal of molecular sciences · 2023Article
- ERK-dependent induction of the immediate-early gene Egr1 and the late gene Gpr50 contribute to two distinct phases of PACAP Gs-GPCR signaling for neuritogenesis.Journal of neuroendocrinology · 2022Article
- Structural Insights into the Intrinsically Disordered GPCR C-Terminal Region, Major Actor in Arrestin-GPCR Interaction.Biomolecules · 2022Article
- Evidence of G-Protein-Coupled Receptors (GPCR) in the Parasitic ProtozoaInternational journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
Transmission of extracellular signals by G protein-coupled receptors typically relies on a cascade of intracellular events initiated by the activation of heterotrimeric G proteins or β-arrestins followed by effector activation/inhibition. Here, we report an alternative signal transduction mode used by the orphan GPR50 that relies on the nuclear translocation of its carboxyl-terminal domain (CTD). Activation of the calcium-dependent calpain protease cleaves off the CTD from the transmembrane-bound GPR50 core domain between Phe-408 and Ser-409 as determined by MALDI-TOF-mass spectrometry. The cytosolic CTD then translocates into the nucleus assisted by its 'DPD' motif, where it interacts with the general transcription factor TFII-I to regulate c-fos gene transcription. RNA-Seq analysis indicates a broad role of the CTD in modulating gene transcription with ~ 8000 differentially expressed genes. Our study describes a non-canonical, direct signaling mode of GPCRs to the nucleus with similarities to other receptor families such as the NOTCH receptor.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.