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PLoS One. 2015 May 13;10(5):e0123581. doi: 10.1371/journal.pone.0123581. eCollection 2015.

FBXO44-Mediated Degradation of RGS2 Protein Uniquely Depends on a Cullin 4B/DDB1 Complex.

Author information

1
Department of Pharmacology & Toxicology, Michigan State University, 1355 Bogue Street, East Lansing, MI 48824, United States of America.
2
Center for Chemical Genomics, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109, United States of America.

Abstract

The ubiquitin-proteasome system for protein degradation plays a major role in regulating cell function and many signaling proteins are tightly controlled by this mechanism. Among these, Regulator of G Protein Signaling 2 (RGS2) is a target for rapid proteasomal degradation, however, the specific enzymes involved are not known. Using a genomic siRNA screening approach, we identified a novel E3 ligase complex containing cullin 4B (CUL4B), DNA damage binding protein 1 (DDB1) and F-box protein 44 (FBXO44) that mediates RGS2 protein degradation. While the more typical F-box partners CUL1 and Skp1 can bind FBXO44, that E3 ligase complex does not bind RGS2 and is not involved in RGS2 degradation. These observations define an unexpected DDB1/CUL4B-containing FBXO44 E3 ligase complex. Pharmacological targeting of this mechanism provides a novel therapeutic approach to hypertension, anxiety, and other diseases associated with RGS2 dysregulation.

PMID:
25970626
PMCID:
PMC4430315
DOI:
10.1371/journal.pone.0123581
[Indexed for MEDLINE]
Free PMC Article

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