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			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
			AR.

			Author Information
			(1) European Molecular Biology Laboratory,
			Heidelberg, Germany.

			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]

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