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

Sjögren B, Swaney S, Neubig RR - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology & Toxicology, Michigan State University, 1355 Bogue Street, East Lansing, MI 48824, 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.

No MeSH data available.


Related in: MedlinePlus

Model of a CUL4B/DDB1/FBXO44 E3 ligase complex responsible for RGS2 protein degradation.FBXO44 also associates with a CUL1/Skp1 complex, however this complex is unable to regulate RGS2 protein degradation.
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pone.0123581.g006: Model of a CUL4B/DDB1/FBXO44 E3 ligase complex responsible for RGS2 protein degradation.FBXO44 also associates with a CUL1/Skp1 complex, however this complex is unable to regulate RGS2 protein degradation.

Mentions: Taken together our data provide strong evidence that RGS2 protein degradation is mediated by a novel CUL4B-DDB1-FBXO44 E3 ligase. Although FBXO44 also associates with a CUL1-Skp1 complex, this E3 ligase complex appears to be incapable of recruiting and degrading RGS2 (Fig 6).


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

Sjögren B, Swaney S, Neubig RR - PLoS ONE (2015)

Model of a CUL4B/DDB1/FBXO44 E3 ligase complex responsible for RGS2 protein degradation.FBXO44 also associates with a CUL1/Skp1 complex, however this complex is unable to regulate RGS2 protein degradation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4430315&req=5

pone.0123581.g006: Model of a CUL4B/DDB1/FBXO44 E3 ligase complex responsible for RGS2 protein degradation.FBXO44 also associates with a CUL1/Skp1 complex, however this complex is unable to regulate RGS2 protein degradation.
Mentions: Taken together our data provide strong evidence that RGS2 protein degradation is mediated by a novel CUL4B-DDB1-FBXO44 E3 ligase. Although FBXO44 also associates with a CUL1-Skp1 complex, this E3 ligase complex appears to be incapable of recruiting and degrading RGS2 (Fig 6).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology & Toxicology, Michigan State University, 1355 Bogue Street, East Lansing, MI 48824, 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.

No MeSH data available.


Related in: MedlinePlus