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  • The EMBO Journal (2005) 24, 1364 - 1374
  • doi:10.1038/sj.emboj.7600616

Published online: 17 March 2005

Thyrotropin receptor trafficking relies on the hScrib–bold betaPIX–GIT1–ARF6 pathway

Olivier Lahuna1,5, Mylène Quellari1,5, Caroline Achard1, Sébastien Nola2, Géri Méduri3, Christel Navarro2, Nicolas Vitale4, Jean-Paul Borg2 and Micheline Misrahi1,3

  1. INSERM E120, Récepteurs, Signalisations et Physiopathologie Thyroïdienne et de la Reproduction, Le Kremlin Bicêtre, France
  2. Molecular Pharmacology, UMR 599 INSERM-Institut Paoli-Calmettes, Marseille, France
  3. Laboratoire d'Hormonologie et Biologie Moléculaire, Hôpital Bicêtre, IFR Bicêtre, Le Kremlin Bicêtre, France
  4. CNRS UPR-2356 Laboratoire Neurotransmission et Sécrétion Neuroendocrine, Centre de Neurochimie, Strasbourg, France
  5. These authors contributed equally to this work

Correspondence to:

Olivier Lahuna, INSERM E120, Récepteurs, Signalisations et Physiopathologie Thyroïdienne et de la Reproduction, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre, France. Tel.: +33 1 49 59 18 52; E-mail: olivier.lahuna@kb.inserm.fr

Jean-Paul Borg, Molecular Pharmacology, UMR 599 INSERM-Institut Paoli-Calmettes, 27 boulevard Lei Roure, 13009 Marseille, France. Tel.: +33 4 91 75 84 09; Fax: +33 4 91 26 03 64; E-mail: borg@marseille.inserm.fr

Micheline Misrahi, INSERM E120, Récepteurs, Signalisations et Physiopathologie Thyroïdienne et de la Reproduction, Hôpital Bicêtre, 94275 Le Kremlin-Bicêtre, France. Tel.: +33 1 45 21 33 29; Fax: +33 1 45 21 38 22; E-mail: micheline.misrahi@bct.ap-hop-paris.fr

Received 31 August 2004; Accepted 14 February 2005

G protein-coupled receptors are regulated by ligand stimulation, endocytosis, degradation of recycling to the cell surface. Little information is available on the molecular mechanisms underlying G protein-coupled receptors recycling. We have investigated recycling of the G protein-coupled thyroid stimulating hormone receptor (TSHR) and found that it relies on hScrib, a membrane-associated PDZ protein. hScrib directly binds to TSHR, inhibits basal receptor endocytosis and promotes recycling, and thus TSHR signalling, at the cell membrane. We previously demonstrated that hScrib is associated with a betaPIX–GIT1 complex comprised of a guanine nucleotide exchange factor and a GTPase-activating protein for ADP ribosylation factors that is involved in vesicle trafficking. We used dominant-negative constructs and small interfering RNA to show that TSHR recycling is regulated by the interaction between hScrib and betaPIX, and by the activity of GIT1. In addition, ARF6, a major target for GIT1, is activated during TSH stimulation of HEK293 and FRTL-5 thyroid cells, and plays a key role in TSHR recycling. Thus, we have uncovered an hScrib–betaPIX–GIT1–ARF6 pathway devoted to TSHR trafficking and function.

  • Keywords:

    • ARF6,
    • PDZ,
    • recycling,
    • Scrib,
    • TSH receptor