GPR50-Ctail cleavage and nuclear translocation: a new signal transduction mode for G protein-coupled receptors

• Published in: Cellular and molecular life sciences : CMLS Vol. 77; no. 24; pp. 5189 - 5205
• Main Authors: Ahmad, Raise, Lahuna, Olivier, Sidibe, Anissa, Daulat, Avais, Zhang, Qiang, Luka, Marine, Guillaume, Jean-Luc, Gallet, Sarah, Guillonneau, François, Hamroune, Juliette, Polo, Sophie, Prévot, Vincent, Delagrange, Philippe, Dam, Julie, Jockers, Ralf
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2020; Springer Nature B.V
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; c-Fos protein; Calcium; Calpain; Cell Biology; Cell Nucleus - genetics; Cell Nucleus - metabolism; Coupled modes; Cytoplasm - genetics; Cytoplasm - metabolism; Domains; Fos gene; G protein-coupled receptors; Humans; Life Sciences; Mass spectrometry; Mass spectroscopy; Nerve Tissue Proteins - genetics; Notch protein; Nuclear transport; Nuclei (cytology); Original; Original Article; Protein Binding - genetics; Protein Transport - genetics; Proteins; Receptors; Receptors, G-Protein-Coupled - genetics; Receptors, Notch; Ribonucleic acid; RNA; Signal transduction; Signal Transduction - genetics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Translocation; Orphan; Signal transduction; GPCR; Calpain; GPR50; Proteolytic cleavage
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-019-03440-7

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