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Insulin and Insulin-Like Growth Factor-I Acutely Inhibit Surface Translocation of Growth Hormone Receptors in Osteoblasts: A Novel Mechanism of Growth Hormone Receptor Regulation
Kin-Chuen Leung, Michael J. Waters, Irit Markus, William R. Baumbach and Ken K. Y. Ho
Proceedings of the National Academy of Sciences of the United States of America
Vol. 94, No. 21 (Oct. 14, 1997), pp. 11381-11386
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/43294
Page Count: 6
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We previously have demonstrated that insulin and insulin-like growth factor-I (IGF-I) down-regulate growth hormone (GH) binding in osteoblasts by reducing the number of surface GH receptors (GHRs). The present study was undertaken to investigate the mechanism of GHR down-regulation. Treatment with 5 nM insulin or IGF-I for 18 hr significantly decreased surface GH binding to 26.4 ± 2.9% and 23.0 ± 2.7% of control (mean ± SE; P < 0.05), respectively. No corresponding reductions in the mRNA level and total cellular content of GHR were found, nor was the rate of receptor internalization affected. The effects on GHR translocation were assessed by measuring the reappearance of GH binding of whole cells after trypsinization to remove the surface receptors. GH binding of control cultures significantly increased (P < 0.05) over 2 hr after trypsinization, whereas no recovery of binding activity was detected in insulin and IGF-I-treated cultures, indicating that GHR translocation was impaired. Studies on the time course of GHR down-regulation revealed that surface GH binding was reduced significantly by 3-hr treatment (P ≤ 0.0005), whereas GHR translocation was completely abolished by 75-90 min with insulin and IGF-I. The inhibition of receptor translocation by insulin, but not IGF-I, was attenuated by wortmannin. In conclusion, insulin and IGF-I down-regulated GH binding in osteoblasts by acutely impairing GHR translocation, with their effects exerted through distinct postreceptor signaling pathways.
Proceedings of the National Academy of Sciences of the United States of America © 1997 National Academy of Sciences