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J. Biol. Chem., Vol. 276, Issue 27, 24565-24573, July 6, 2001
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From the § Department of Medicine, Division of
Endocrinology and Metabolism and Growth hormone (GH) initiates its cellular action
by properly dimerizing GH receptor (GHR). A substantial fraction of
circulating GH is complexed with a high-affinity GH-binding protein
(GHBP) that in many species can be generated by GHR proteolysis and
shedding of the receptor's ligand-binding extracellular domain. We
previously showed that this proteolysis 1) can be acutely promoted by
the phorbol ester phorbol 12-myristate 13-acetate (PMA), 2) requires a
metalloprotease activity, 3) generates both shed GHBP and a membrane-associated GHR transmembrane/cytoplasmic domain remnant, and
4) results in down-regulation of GHR abundance and GH signaling. Using
cell culture model systems, we now explore the effects of GH treatment
on inducible GHR proteolysis and GHBP shedding. In human IM-9
lymphocytes, which endogenously express GHRs, and in Chinese hamster
ovary cells heterologously expressing wild-type or cytoplasmic domain
internal deletion mutant rabbit GHRs, brief exposure to GH inhibited
PMA-induced GHR proteolysis (receptor loss and remnant accumulation) by
60-93%. PMA-induced shedding of GHBP from Chinese hamster ovary
transfectants was also inhibited by 70% in the presence of GH. The
capacity of GH to inhibit inducible GHR cleavage did not rely on
JAK2-dependent GH signaling, as evidenced by its
continued protection in JAK2-deficient
Growth Hormone (GH)-induced Dimerization Inhibits Phorbol
Ester-stimulated GH Receptor Proteolysis*
,,§§, and§¶¶
Department of Cell
Biology, University of Alabama at Birmingham, Birmingham, Alabama
35294, ¶¶ Veterans Affairs Medical Center, Birmingham,
Alabama 35294, ¶ Edison Biotechnology Institute and Department of
Biomedical Sciences, College of Osteopathic Medicine, Ohio
University, Athens, Ohio 45701, ** Immunex Corp., Seattle,
Washington 98101, Center for
Endocrinology, Metabolism, and Molecular Medicine, Department of
Medicine, Northwestern University Medical School, Chicago, Illinois
60611, and §§ Veterans Administration Chicago
Health System, Lakeside Division, Chicago, Illinois 60611
2A rabbit GHR cells. The GH concentration dependence for inhibition of PMA-induced GHR
proteolysis paralleled that for its promotion of receptor dimerization
(as monitored by formation of GHR disulfide linkage). Unlike GH, the GH
antagonist, G120K, which binds to but fails to properly dimerize GHRs,
alone did not protect against PMA-induced GHR proteolysis; G120K did,
however, antagonize the protective effect of GH. Our data suggest that
GH inhibits PMA-induced GHR proteolysis and GHBP shedding by inducing
GHR dimerization and that this effect does not appear to be related to
GH site 1 binding, GHR internalization, or GHR signaling. The
implications of these findings with regard to GH signaling and
GHR down-regulation are discussed.
*
This work was supported in part by VA Merit Review awards
(to S. J. F. and G. B.), grants from the National Science Foundation and the Northwestern Memorial Foundation (to G. B.), National Institutes of Health Grant DK46395 (to S. J. F.), and the State of
Ohio Eminent Scholar Program, which includes a grant from Milton and
Lawrence Goll, and by Sensus Corp. (to J. J. K.).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.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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