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

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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Acknowledgements

We are grateful to Dr. Mark Scott (Institut Cochin, France) for expert advice and Cédric Broussard and Morgane Le Gall from the Plateform Protéomique 3P5 for protein identification by mass spectrometry and Franck Letourneur and Benjamin Saintpierre from the Genomic Facility of the Institut Cochin. This work was supported by grants from the Fondation Recherche Médicale (Equipe FRM 2006 to RJ), ARC No. NSFI20121205906, Agence Nationale de la Recherche (ANR-16-CE18-0013 to JD) and the “Who am I?” laboratory of excellence No.ANR-11-LABX-0071 funded by the French Government through its “Investments for the Future” program operated by The French National Research Agency under Grant No. ANR-11-IDEX-0005-01 (to RJ and RA), Inserm and CNRS.

Author information

RA, OL, AS, JLG, PD, and RJ: conceptualization. RA, OL, AS, QZ, ML, SG, FG, and FL: investigation. FG, FL, VP, and PD: resources. RA and RJ: writing—original draft. RA, OL, SP, PD, JD, and RJ: writing—review and editing. PD, SP, JD, and RJ: funding acquisition. RA, OL, FG, FL, SP, VP, PD, JD, and RJ: supervision.

Correspondence to Ralf Jockers.

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Ahmad, R., Lahuna, O., Sidibe, A. et al. GPR50-Ctail cleavage and nuclear translocation: a new signal transduction mode for G protein-coupled receptors. Cell. Mol. Life Sci. (2020). https://doi.org/10.1007/s00018-019-03440-7

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Keywords

  • GPCR
  • Orphan
  • Calpain
  • GPR50
  • Proteolytic cleavage
  • Signal transduction