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The Ubiquitin-Proteasome Pathway Regulates the Availability of the GH Receptor

Department of Cell Biology and Institute of Biomembranes (P.v.K., G.J.S.), Experimental Cardiology Laboratory (M.S.), Interuniversity Cardiology Institute of the Netherlands (ICIN), University Medical Center Utrecht, Heidelberglaan 100, AZU-G02.525, 3584CX Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Ger J. Strous, Ph.D., University Medical Center Utrecht, Department of Cell Biology, Heidelberg 100, AZU, G02.525, Utrecht 3584 CX, The Netherlands. e-mail: . strous{at}med.uu.nl

GH promotes not only longitudinal growth in children but is active throughout life in protein, fat, and carbohydrate metabolism. The multiple actions of GH start when GH binds to the cell surface-expressed GH receptor. Effectiveness of the hormone depends both on its presence in the circulation and the availability of receptors at the cell surface of target cells. In this study, we examined the role of the ubiquitin-proteasome pathway in regulating GH receptor availability. We show that receptor turnover is rapid, and almost 3-fold prolonged in the internalization-deficient mutant GH receptor (F327A). Using a monovalent GH antagonist, B2036, we could quantify the internalization of the nonactivated receptor. By comparing internalization of the receptor with shedding of the GH-binding protein, we show that in Chinese hamster lung cell lines, internalization followed by lysosomal degradation is the major pathway for receptor degradation and that the ubiquitin-proteasome pathway controls this process. Inhibition of endocytosis resulted in a 200% increase in receptor availability at the cell surface at steady state.

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