Journal
MOLECULAR CELL
Volume 58, Issue 5, Pages 794-803Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2015.04.017
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Funding
- Chinese Ministry of Sciences and Technology 973 [2015CB910401, 2011CB910600]
- NSFC [31271454, 81225016, 81430057]
- Shanghai Key basic research program [12JC1401100]
- Shanghai Outstanding Academic Leader [13XD1400600]
- Youth Science and Technology Leading Talent by MOST
- NIH [EY022611, CA132809, GM067113]
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G protein-coupled receptors (GPCRs) comprise the largest family of cell surface receptors, regulate a wide range of physiological processes, and are the major targets of pharmaceutical drugs. Canonical signaling from GPCRs is relayed to intracellular effector proteins by trimeric G proteins, composed of alpha, beta, and gamma subunits (G alpha beta gamma). Here, we report that G protein beta subunits (G beta) bind to DDB1 and that G beta 2 targets GRK2 for ubiquitylation by the DDB1-CUL4A-ROC1 ubiquitin ligase. Activation of GPCR results in PKA-mediated phosphorylation of DDB1 at Ser645 and its dissociation from G beta 2, leading to increase of GRK2 protein. Deletion of Cul4a results in cardiac hypertrophy in male mice that can be partially rescued by the deletion of one Grk2 allele. These results reveal a non-canonical function of the Gb protein as a ubiquitin ligase component and a mechanism of feedback regulation of GPCR signaling.
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