GPR50-Ctail cleavage and nuclear translocation: a new signal transduction mode for G protein-coupled receptors.
Cell Mol Life Sci
; 77(24): 5189-5205, 2020 Dec.
Article
em En
| MEDLINE
| ID: mdl-31900622
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 ß-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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Base de dados:
MEDLINE
Assunto principal:
Transporte Proteico
/
Receptores Acoplados a Proteínas G
/
Proteínas do Tecido Nervoso
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article