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J. Biol. Chem., Vol. 279, Issue 27, 28499-28508, July 2, 2004

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Low Levels of Expression of Leptin Receptor at the Cell Surface Result from Constitutive Endocytosis and Intracellular Retention in the Biosynthetic Pathway^*

Sandrine Belouzard, Delphine Delcroix¶, and Yves Rouillé¶||

From the Unité Propre de Recherche 2511 and ^¶Equipe Postulante 525, Institut de Biologie de Lille, CNRS, 59021 Lille, France

The leptin receptor is mainly localized in intracellular compartments in target tissues. To study the mechanisms leading to this intracellular localization, two main isoforms of leptin receptors, OB-Ra and OB-Rb, were expressed in HeLa cells. Both isoforms were localized at steady state in the trans-Golgi network, in endosomes, and to a lesser extent, at the cell surface. They turned over with a half-life of less than 2 h. Both isoforms of leptin receptors were constitutively endocytosed in a ligand-independent manner and degraded in lysosomes with no evidence of recycling to the cell surface or to the trans-Golgi network. The endocytosis was inhibited by the deletion of the cytoplasmic domain. Newly synthesized leptin receptors were partially retained in the Golgi complex or in a post-Golgi intracellular compartment. The transmembrane domain was found to be important for this intracellular retention in the biosynthetic pathway, whereas the cytoplasmic domain was not involved. The data suggest that the low levels of expression of leptin receptors at the cell surface results from partial retention in the biosynthetic pathway, coupled to constitutive removal from the plasma membrane via ligand-independent, constitutive endocytosis.

Received for publication, January 16, 2004 , and in revised form, April 16, 2004.

^* This work was supported by the Centre National de la Recherche Scientifique. 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.

Recipient of financial support from the Fondation pour la Recherche Médicale.

^|| To whom correspondence should be addressed. E-mail: yves.rouille{at}ibl.fr.

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