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PNAS 99 (15): 9858-9863

Copyright © 2002 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

Ligand-independent growth hormone receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis

Jürgen Gent*, Peter van Kerkhof*, Marcel Roza*, Guojun Bu{dagger}, and Ger J. Strous*,{ddagger}

*Department of Cell Biology and Institute of Biomembranes, University Medical Center, 3584 CX, Utrecht, The Netherlands; and {dagger}Departments of Pediatrics, Cell Biology, and Physiology, Washington University School of Medicine, St. Louis, MO 63110

Accepted for publication May 16, 2002.

Received for publication December 23, 2001.

Abstract: The regulatory effect of growth hormone (GH) on its target cells is mediated via the GH receptor (GHR). GH binding to the GHR results in the formation of a GH-(GHR)2 complex and the initiation of signal transduction cascades via the activation of the tyrosine kinase JAK2. Subsequent endocytosis and transport to the lysosome of the ligand-receptor complex is regulated via the ubiquitin system and requires the presence of an intact ubiquitin-dependent endocytosis (UbE) motif in the cytosolic tail of the GHR. Recently, the model of ligand-induced receptor dimerization has been challenged. In this study, ligand-independent GHR dimerization is demonstrated in the endoplasmic reticulum and at the cell surface by coimmunoprecipitation of an epitope-tagged truncated GHR with wild-type GHR. In addition, evidence is provided that the extracellular domain of the GHR is not required to maintain this interaction. Internalization of a chimeric receptor, which fails to dimerize, is independent of an intact UbE-motif. Therefore, we postulate that dimerization of GHR molecules is required for ubiquitin system-dependent endocytosis.

{ddagger} To whom reprint requests may be addressed. E-mail: strous{at}med.uu.nl.

Communicated by Harvey F. Lodish, Massachusetts Institute of Technology, Cambridge, MA

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