Jak2 and proteasome activities control the availability of cell surface growth hormone receptors during ligand exposure.
Several mechanisms participate in the down-regulation of growth hormone receptor (GHR) signalling under ligand exposure. In CHO cells expressing GHR, we show that ligand stimulation induces degradation of the total cell GHR content. Experiments with 125I-hGH indicate that ligand-bound internalized receptors are not immediately replaced. Using cell surface biotinylation, we demonstrate for the first time that, concomitantly with the degradation of cell surface receptors, GHRs from the intracellular compartments are also degraded. We thus suggest that under prolonged ligand exposure, some GHRs are targeted to the cell surface, while others are routed to degradation compartments. Inhibitors of Jak2 and of the proteasome partially inhibited degradation of cell surface receptors, while these compounds completely inhibit the degradation of intracellular GHRs, resulting in their accumulation. We therefore propose that Jak2 and proteasome activities control the amount of intracellular GHRs, and thus the availability of receptors at the cell surface, during ligand exposure.
Moulin
Stéphanie
S
INSERM Unit 344, Molecular Endocrinology, Faculty of Medicine Necker, 156 rue de Vaugirard 75730, Paris Cedex 15, France.
Bouzinba-Segard
Haniaa
H
Kelly
Paul A
PA
Finidori
Joëlle
J
D000818:Animals; D016466:CHO Cells; D002451:Cell Compartmentation; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000378:metabolism* / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D013006:Growth Hormone / Q000378:metabolism; D053614:Janus Kinase 2; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D008024:Ligands; D009097:Multienzyme Complexes; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex