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24 (18): 3235-3246

Copyright © 2005 by the European Molecular Biology Organization.

Phosphorylation of EEA1 by p38 MAP kinase regulates µ opioid receptor endocytosis

Gaëtane Macé1,2,4, Marta Miaczynska3,5, Marino Zerial3, and Angel R Nebreda1,2,+

1 European Molecular Biology Laboratory, Heidelberg, Germany
2 CNIO (Spanish National Cancer Center), Madrid, Spain
3 Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany

Abstract: Morphine analgesic properties and side effects such as tolerance are mediated by the µ 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{alpha}–/– cells. We found that p38{alpha} 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{alpha} in MOR endocytosis. Our results highlight a novel mechanism whereby p38 MAPK regulates receptor endocytosis under physiological conditions via phosphorylation of Rab5 effectors.

Key Words: EEA1 • endocytosis • MAP kinase • Rab5 • signalling

4 Present address: Institut Gustave Roussy-CNRS UPR2169, 94805 Villejuif Cedex, France

5 Present address: International Institute of Molecular and Cell Biology, Ks. Trojdena 4, 02-109 Warsaw, Poland

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