| First Author | Zha Z | Year | 2015 |
| Journal | Mol Cell | Volume | 58 |
| Issue | 5 | Pages | 794-803 |
| PubMed ID | 25982117 | Mgi Jnum | J:226132 |
| Mgi Id | MGI:5695822 | Doi | 10.1016/j.molcel.2015.04.017 |
| Citation | Zha Z, et al. (2015) A Non-Canonical Function of Gbeta as a Subunit of E3 Ligase in Targeting GRK2 Ubiquitylation. Mol Cell 58(5):794-803 |
| abstractText | 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 (Galphabetagamma). Here, we report that G protein beta subunits (Gbeta) bind to DDB1 and that Gbeta2 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 Gbeta2, 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 Gbeta protein as a ubiquitin ligase component and a mechanism of feedback regulation of GPCR signaling. |
