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