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J Biol Chem, Vol. 274, Issue 21, 14791-14798, May 21, 1999
From the Divisions of Clinical Sciences and § Molecular
and Genetic Medicine, Sheffield University, Sheffield S5 7AU, United
Kingdom and We have investigated trafficking of two negative
regulators of growth hormone receptor (GHR) signaling: a human,
truncated receptor, GHR1-279, and a GH antagonist, B2036.
Fluorescent-labeled growth hormone (GH) was rapidly internalized by the
full-length GHR, with >80% of the hormone internalized within 5 min
of exposure to GH. In contrast, <5% of labeled GH was internalized by
cells expressing truncated GHR1-279. Using another truncated receptor, GHR1-317 fused to enhanced green fluorescent protein (EGFP), we have
exploited fluorescence energy transfer to monitor the trafficking of
ligand-receptor complexes. The data confirmed that internalization of
this truncated receptor is very inefficient. It was possible to
visualize the truncated GHR1-317-EGFP packaged in the endoplasmic reticulum, its rapid movement in membrane bound vesicles to the Golgi
apparatus, and subsequent transport to the cell membrane. The GH
antagonist, B2036, blocked Jak2-Stat5-mediated GHR signaling but was
internalized with a similar time course to native GH. The results: 1)
demonstrate the rapid internalization of GH when studied under
physiological conditions; 2) confirm the hypothesis that
internalization of cytoplasmic domain truncated human GHRs is very
inefficient, which explains their dominant negative action; and 3) show
that the antagonist action of B2036 is independent of receptor internalization.
Studies with a Growth Hormone Antagonist and Dual-fluorescent
Confocal Microscopy Demonstrate that the Full-length Human Growth
Hormone Receptor, but Not the Truncated Isoform, Is Very Rapidly
Internalized Independent of Jak2-Stat5 Signaling
, INSERM Unite 344, Endocrinologie Moleculaire,
Faculte de Medecine Necker, 75730 Paris Cedex 15, France
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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