title: Ligand-independent growth hormone receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis.
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.
authors.affiliation: Department of Cell Biology and Institute of Biomembranes, University Medical Center, 3584 CX, Utrecht, The Netherlands.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Gent
authors.forename: Peter
authors.initials: P
authors.lastname: van Kerkhof
authors.forename: Marcel
authors.initials: M
authors.lastname: Roza
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: Ger J
authors.initials: GJ
authors.lastname: Strous
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019281:Dimerization; D004705:Endocytosis / Q000502:physiology*; D019286:Endopeptidase K; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D013006:Growth Hormone / Q000378:metabolism; D053614:Janus Kinase 2; D007700:Kinetics; D008024:Ligands; D008247:Lysosomes / Q000502:physiology; D008958:Models, Molecular; D016296:Mutagenesis; D011487:Protein Conformation; D021122:Protein Subunits; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011817:Rabbits; D011986:Receptors, Somatotropin / Q000737:chemistry* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015183:Restriction Mapping; D015398:Signal Transduction / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D008024:Ligands; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D011994:Recombinant Proteins; D025801:Ubiquitin; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2; D019286:Endopeptidase K