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J. Biol. Chem., Vol. 279, Issue 13, 12636-12646, March 26, 2004

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Receptor Trafficking via the Perinuclear Recycling Compartment Accompanied by Cell Division Is Necessary for Permanent Neurotensin Cell Sensitization and Leads to Chronic Mitogen-activated Protein Kinase Activation^*

Mireille Toy-Miou-Leong, Catherine Llorens Cortes¶, Alain Beaudet||, William Rostène**, and Patricia Forgez

From the INSERM Unit 482, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, ^¶INSERM Unit 36, Collège de France, 3 Rue d'Ulm, 75005 Paris, France, ^||Montreal Neurological Institute, McGill University, Montreal, Quebec H2A2B4, Canada, and ^**INSERM EMI 0350, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, France

Most G protein-coupled receptors are internalized after interaction with their respective ligand, a process that subsequently contributes to cell desensitization, receptor endocytosis, trafficking, and finally cell resensitization. Although cellular mechanisms leading to cell desensitization have been widely studied, those responsible for cell resensitization are still poorly understood. We examined here the traffic of the high affinity neurotensin receptor (NT1 receptor) following prolonged exposure to high agonist concentration. Fluorescence and confocal microscopy of Chinese hamster ovary, human neuroblastoma (CHP 212), and murine neuroblastoma (N1E-115) cells expressing green fluorescent protein-tagged NT1 receptor revealed that under prolonged treatment with saturating concentrations of neurotensin (NT) agonist, NT1 receptor and NT transiently accumulated in the perinuclear recycling compartment (PNRC). During this cellular event, cell surface receptors remained markedly depleted as detected by both confocal microscopy and ¹²⁵I-NT binding assays. In dividing cells, we observed that following prolonged NT agonist stimulation, NT1 receptors were removed from the PNRC, accumulated in dispersed vesicles inside the cytoplasm, and subsequently reappeared at the cell surface. This NT binding recovery allowed for constant cell sensitization and led to a chronic activation of mitogen-activated protein kinases p42 and p44. Under these conditions, the constant activation of NT1 receptor generates an oncogenic regulation. These observations support the potent role for neuropeptides, such as NT, in cancer progression.

Received for publication, April 2, 2003 , and in revised form, December 22, 2003.

^* This work was supported in part by INSERM and "Association pour la Recherche sur le Cancer" Grant 9397. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by INSERM and a fellowship from Association pour la Recherche sur le Cancer.

To whom correspondence should be addressed: INSERM Unit 482, Hôpital Saint-Antoine, 184 Rue du Faubourg St.-Antoine, 75012 Paris, France. Tel.: 33 1 49 28 46 74; Fax: 33 1 44 74 93 18; E-mail: forgez{at}st-antoine.inserm.fr.

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