Moulin Stéphanie, Bouzinba-Segard Haniaa, Kelly Paul A, Finidori Joëlle
INSERM Unit 344, Molecular Endocrinology, Faculty of Medicine Necker, 156 rue de Vaugirard 75730, Paris Cedex 15, France.
Cell Signal. 2003 Jan;15(1):47-55. doi: 10.1016/s0898-6568(02)00054-2.
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.
在配体暴露情况下，多种机制参与生长激素受体（GHR）信号传导的下调。在表达GHR的CHO细胞中，我们发现配体刺激会诱导总细胞GHR含量的降解。用¹²⁵I-hGH进行的实验表明，结合配体的内化受体不会立即被替换。通过细胞表面生物素化，我们首次证明，在细胞表面受体降解的同时，细胞内区室中的GHR也会被降解。因此，我们认为在长时间配体暴露下，一些GHR靶向细胞表面，而另一些则被导向降解区室。Jak2和蛋白酶体的抑制剂部分抑制细胞表面受体的降解，而这些化合物完全抑制细胞内GHR的降解，导致其积累。因此，我们提出在配体暴露期间，Jak2和蛋白酶体活性控制细胞内GHR的数量，从而控制细胞表面受体的可用性。
