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J Biol Chem, Vol. 273, Issue 26, 16426-16433, June 26, 1998

Di-leucine-mediated Internalization of Ligand by a Truncated Growth Hormone Receptor Is Independent of the Ubiquitin Conjugation System

Roland Govers, Peter van Kerkhof, Alan L. Schwartz, and Ger J. Strous

From the Department of Cell Biology, Faculty of Medicine and Institute of Biomembranes, Utrecht University, 3584 CX Utrecht, The Netherlands and the  Departments of Molecular Biology, Pharmacology and Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110

The growth hormone receptor (GHR) is a member of the cytokine receptor family. Its function is to mediate cellular responses upon binding of growth hormone. Ligand binding induces dimerization and activation of the GHR. One mechanism by which the GHR is rapidly inactivated involves the ubiquitin conjugation system, a system implicated in the degradation of cytosolic and nuclear proteins. We have shown previously that the ubiquitin-conjugating system mediates internalization of the GHR. Here, we present evidence that in addition to the ubiquitin-dependent endocytosis signal, the cytosolic tail of the GHR contains a di-leucine motif. Upon truncation of the GHR at amino acid residue 349, this di-leucine motif is activated and mediates ubiquitin-independent internalization of the receptor. Di-leucine-mediated GHR internalization requires functional clathrin-coated pits and results in GHR transport to the lysosome. Although the full-length GHR internalizes independent of the di-leucine motif, this motif may function in internalization of GHR isoforms.

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