Clear Search sequence regions

Sizes of these terms reflect their relevance to your search.

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 α, β, and γ subunits (Gαβγ). Here, we report that G protein β subunits (Gβ) bind to DDB1 and that Gβ2 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 Gβ2, 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 protein as a ubiquitin ligase component and a mechanism of feedback regulation of GPCR signaling. Copyright © 2015 Elsevier Inc. All rights reserved.


Zhengyu Zha, Xiaoran Han, Matthew D Smith, Yang Liu, Patrick M Giguère, Dragana Kopanja, Pradip Raychaudhuri, David P Siderovski, Kun-Liang Guan, Qun-Ying Lei, Yue Xiong. A Non-Canonical Function of Gβ as a Subunit of E3 Ligase in Targeting GRK2 Ubiquitylation. Molecular cell. 2015 Jun 4;58(5):794-803

Expand section icon Mesh Tags

Expand section icon Substances

PMID: 25982117

View Full Text