PubMed Journals: EMBO J
Source: PMID: 16138080
⇦ ⇨ EMBO J. 2005 Sep 21;24(18):3235-46. Epub
⇩ 2005 Sep 1.
Phosphorylation of EEA1 by p38 MAP kinase
regulates mu opioid receptor endocytosis.
Macé G(1), Miaczynska M, Zerial M, Nebreda
(1) European Molecular Biology Laboratory,
Morphine analgesic properties and side effects
such as tolerance are mediated by the mu
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 p38alpha-/- cells.
We found that p38alpha 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 p38alpha
in MOR endocytosis. Our results highlight
a novel mechanism whereby p38 MAPK regulates
receptor endocytosis under physiological conditions
via phosphorylation of Rab5 effectors.
DOI: 10.1038/sj.emboj.7600799 PMCID: PMC1224689
PMID: 16138080 [Indexed for MEDLINE]