Article
- The EMBO Journal (2005) 24, 3235 - 3246
- doi:10.1038/sj.emboj.7600799
Published online: 1 September 2005
Subject Categories:
Phosphorylation of EEA1 by p38 MAP kinase regulates 
opioid receptor endocytosis
Gaëtane Macé1,2,a, Marta Miaczynska3,b, Marino Zerial3 and Angel R Nebreda1,2
- European Molecular Biology Laboratory, Heidelberg, Germany
- CNIO (Spanish National Cancer Center), Madrid, Spain
- Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany
Correspondence to:
Angel R Nebreda, CNIO (Spanish National Cancer Center), Melchor Fernández Almagro 3, 28029 Madrid, Spain. Tel.: +34 91 7328038; Fax: +34 91 7328033; E-mail: anebreda@cnio.es
aPresent address: Institut Gustave Roussy-CNRS UPR2169, 94805 Villejuif Cedex, France
bPresent address: International Institute of Molecular and Cell Biology, Ks. Trojdena 4, 02-109 Warsaw, Poland
Received 9 March 2005; Accepted 8 August 2005
Abstract
Morphine analgesic properties and side effects such as tolerance are mediated by the 
opioid receptor (MOR) whose endocytosis is considered of primary importance for opioid pharmacological effects. Here, we show that p38 mitogen-activated protein kinase (MAPK) activation is required for MOR endocytosis and sufficient to trigger its constitutive internalization in the absence of agonist. Further studies established a functional link between p38 MAPK and the small GTPase Rab5, a key regulator of endocytosis. Expression of an activated mutant of Rab5 stimulated endocytosis of MOR ligand-independently in wild-type but not in p38
-/- cells. We found that p38 can phosphorylate the Rab5 effectors EEA1 and Rabenosyn-5 on Thr-1392 and Ser-215, respectively, and these phosphorylation events regulate the recruitment of EEA1 and Rabenosyn-5 to membranes. Moreover, phosphomimetic mutation of Thr-1392 in EEA1 can bypass the requirement for p38 in MOR endocytosis. Our results highlight a novel mechanism whereby p38 MAPK regulates receptor endocytosis under physiological conditions via phosphorylation of Rab5 effectors.
Keywords:
- EEA1,
- endocytosis,
- MAP kinase,
- Rab5,
- signalling
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