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GPR50-Ctail cleavage and nuclear translocation: a new signal transduction mode for G protein-coupled receptors
- Source :
- Cellular and molecular life sciences : CMLS. 77(24)
- Publication Year :
- 2019
-
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.
- Subjects :
- Cytoplasm
Notch signaling pathway
Nerve Tissue Proteins
Receptors, G-Protein-Coupled
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Heterotrimeric G protein
Humans
Molecular Biology
030304 developmental biology
G protein-coupled receptor
Pharmacology
Cell Nucleus
0303 health sciences
General transcription factor
Receptors, Notch
Chemistry
Effector
Cell Biology
Cell biology
Protein Transport
GPR50
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Molecular Medicine
CTD
Signal transduction
030217 neurology & neurosurgery
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 14209071
- Volume :
- 77
- Issue :
- 24
- Database :
- OpenAIRE
- Journal :
- Cellular and molecular life sciences : CMLS
- Accession number :
- edsair.doi.dedup.....5d545a75b85862c90a86b17ead3a500c