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Originally published In Press as doi:10.1074/jbc.M208738200 on October 25, 2002

J. Biol. Chem., Vol. 277, Issue 52, 50510-50519, December 27, 2002
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Metalloprotease-mediated GH Receptor Proteolysis and GHBP Shedding
DETERMINATION OF EXTRACELLULAR DOMAIN STEM REGION CLEAVAGE SITE*

Xiangdong WangDagger , Kai HeDagger , Mary Gerhart§, Yao HuangDagger , Jing JiangDagger , Raymond J. Paxton§, Shaohua Yang, Chunxia Lu, Ram K. Menon, Roy A. Black§, Gerhard Baumann||, and Stuart J. FrankDagger **Dagger Dagger

From the Dagger  Department of Medicine, Division of Endocrinology and Metabolism, and Department of Cell Biology, University of Alabama at Birmingham, Alabama 35294, the § Immunex Corporation, Seattle, Washington 98101, the  Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, the || Center for Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Medical School and the Veterans Administration Chicago Health System, Lakeside Division, Chicago, Illinois 60611, and the ** Endocrinology Section, Medical Service, Veterans Affairs Medical Center, Birmingham, Alabama 35233

Growth hormone-binding protein (GHBP) is complexed to a substantial fraction of circulating GH. In humans, rabbits, and other species, GHBP derives from proteolytic shedding of the GH receptor (GHR) extracellular domain. In cell culture studies, stimuli such as phorbol ester, platelet-derived growth factor, or serum induce GHR proteolysis, which concomitantly yields shed GHBP in cell supernatants and a cell-associated cytoplasmic domain-containing GHR remnant. This process is sensitive to metalloprotease inhibition, and genetic reconstitution studies identify tumor necrosis factor-alpha converting enzyme (TACE/ADAM-17), a transmembrane metalloprotease, as a GHR sheddase. Stimuli that induce GHR proteolysis render cells less responsive to GH, but the mechanism(s) of this desensitization is not yet understood. In this study, we mapped the rabbit (rb) GHR cleavage site. We adenovirally expressed a C-terminal epitope-tagged rbGHR lacking most of its cytoplasmic domain, purified the remnant protein induced by the phorbol ester, PMA, and derived the cleavage site by N-terminal sequencing of the purified remnant. The N-terminal sequence, 239FTCEEDFR246, matched perfectly the rbGHR and suggests that cleavage occurs eight residues from the membrane in the proximal extracellular domain stem region. Deletion and alanine substitution mutagenesis indicated that, similar to other TACE substrates, the spacing of residues in this region, more than their identity, influences GHR cleavage susceptibility. Further, we determined that PMA pretreatment desensitized a cleavage-sensitive GHR mutant, but not a cleavage-insensitive mutant, to GH-induced JAK2 activation. These results suggest that inducible GHR proteolysis can regulate GH signaling.

* This work was supported by Veterans Affairs Merit Review awards (to S. J. F. and G. B.), a grant from the National Science Foundation (to G. B.), and National Institutes of Health Grants DK46395 and DK58259 (to S. J. F.). Parts of this work were presented at the 84th Annual Endocrine Society Meetings in San Francisco, CA 2002.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Dagger To whom correspondence should be addressed: University of Alabama at Birmingham, 1530 3rd Ave. South, BDB 861, Birmingham, AL 35294-0012. Tel.: 205-934-9877; Fax: 205-934-4389; E-mail: frank@endo.dom.uab.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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