Imperial College London
Alternate

ProfessorPeterO'Hare

Faculty of Medicine, Department of Infectious Disease

Chair in Virology
 
 
 
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Contact

 

+44 (0)20 7594 9517p.ohare Website

 
 
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Location

 

Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@article{Barbosa:2015:10.1091/mbc.E15-04-0247,
author = {Barbosa, S and Carreira, S and Bailey, D and Abaitua, F and O'Hare, P},
doi = {10.1091/mbc.E15-04-0247},
journal = {Molecular Biology of the Cell},
pages = {2939--2954},
title = {Phosphorylation and SCF-mediated degradation regulate CREB-H transcription of metabolic targets.},
url = {http://dx.doi.org/10.1091/mbc.E15-04-0247},
volume = {26},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - CREBH, an endoplasmic reticulum-anchored transcription factor, plays a key role in regulating secretion and in metabolic and inflammatory pathways, but how its activity is modulated remains unclear. We examined processing of the nuclear active form and identified a motif around S87-S90 with homology to DSG-type phosphodegrons. We show that this region is subject to multiple phosphorylations, which regulate CREB-H stability by targeting it to the SCF(Fbw1a) E3 ubiquitin ligase. Data from phosphatase treatment, use of phosophospecific antibody, and substitution of serine residues demonstrate phosphorylation of candidate serines in the region, with the core S87/S90 motif representing a critical determinant promoting proteasome-mediated degradation. Candidate kinases CKII and GSK-3b phosphorylate CREB-H in vitro with specificities for different serines. Prior phosphorylation with GSK-3 at one or more of the adjacent serines substantially increases S87/S90-dependent phosphorylation by CKII. In vivo expression of a dominant-negative Cul1 enhances steady-state levels of CREBH, an effect augmented by Fbw1a. CREB-H directly interacts with Fbw1a in a phosphorylation-dependent manner. Finally, mutations within the phosphodegron, when incorporated into the full-length protein, result in increased levels of constitutively cleaved nuclear protein and increased transcription and secretion of a key endogenous target gene, apolipoprotein A IV.
AU  - Barbosa,S
AU  - Carreira,S
AU  - Bailey,D
AU  - Abaitua,F
AU  - O'Hare,P
DO  - 10.1091/mbc.E15-04-0247
EP  - 2954
PY  - 2015///
SN  - 1939-4586
SP  - 2939
TI  - Phosphorylation and SCF-mediated degradation regulate CREB-H transcription of metabolic targets.
T2  - Molecular Biology of the Cell
UR  - http://dx.doi.org/10.1091/mbc.E15-04-0247
UR  - http://hdl.handle.net/10044/1/25915
VL  - 26
ER  -
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