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Autocrine Growth Hormone: Effects on Growth Hormone Receptor Trafficking and Signaling

Department of Cell Biology, Institute of Biomembranes, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Ger J. Strous, Department of Cell Biology, University Medical Center Utrecht, Heidelberglaan 100, Room G02.525, 3584 CX Utrecht, The Netherlands. E-mail: gstrous{at}umcutrecht.nl.

GH and GH receptor are expressed in many extrapituitary tissues, permitting autocrine/paracrine activity. Autocrine GH has regulatory functions in embryonic development and cellular differentiation and proliferation and is reported to be involved in the development and metastasis of tumor cells. To understand the principles of transport and signaling of autocrine GH and GH receptor, we used a model system to express both proteins in the same cell. Our experiments show that GH binds the GH receptor immediately after synthesis in the endoplasmic reticulum and facilitates maturation of GH receptor. The hormone-receptor complexes arrive at the cell surface where exogenously added GH is unable to bind these receptors. Autocrine GH activates the GH receptors, but signal transduction occurs only after exiting the endoplasmic reticulum. This model study explains why autocrine GH-producing cells may be insensitive for GH (antagonist) treatment and clarifies autocrine signaling events.