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, Ger J. Strous

Research output: Contribution to journalArticlepeer-review

148 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)9858-9863
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number15
DOIs
StatePublished - Jul 23 2002

ASJC Scopus subject areas

  • General

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