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Department of Medicine, Division of Endocrinology and Metabolism (J.A., J.J., J.F.G., S.J.F.), and the Department of Cell Biology (X.Y., S.J.F.), University of Alabama, and the Veterans Affairs Medical Center (J.F.G., S.J.F.), Birmingham, Alabama 35294; the Center for Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Medical School (H.G.M., G.B.), Chicago, Illinois 60611; and Immunex Corp. (R.A.B.), Seattle, Washington 98101
Address all correspondence and requests for reprints to: Dr. Stuart J. Frank, University of Alabama, Room 756, Diabetes Research and Education Building, UAB Station, Birmingham, Alabama 35294. E-mail: frank{at}endo.dom.uab.edu
GH, an important growth-promoting and metabolic hormone, exerts its
biological effects by interacting with cell surface GH receptors
(GHRs). The GHR is a single membrane-spanning protein that binds GH via
its extracellular domain. The high affinity GH-binding protein (GHBP),
which corresponds to a soluble form of the GHR extracellular domain,
carries a substantial fraction of the GH in the circulation of various
species and probably has a role in modulation of the hormone’s
bioavailability. Although in rodents, it is believed that the GHBP is
largely derived by translation of an alternatively spliced GHR
messenger RNA, in humans and rabbits, proteolytic cleavage of the
membrane-anchored receptor releases the GHR extracellular domain, which
is believed to thereby become the GHBP. In this study, we used human
IM-9 lymphocytes and GHR antibodies to study this proteolytic shedding
of the GHBP. As determined by immunoblotting with anti-GHR cytoplasmic
domain serum, addition of phorbol 12-myristate 13-acetate (PMA; 1
µg/ml) to serum-starved cells led to rapid loss (roughly 60% decline
after 1 h; t1/2 = 
5 min) of mature GHRs (115–140
kDa) from either total cell or detergent-soluble extracts. Loss of
full-length GHRs was accompanied by accumulation of four proteins
(65–68 kDa), each reactive with the cytoplasmically directed
antiserum. The pattern of appearance of these GHR ctyoplasmic domain
proteins, the electrophoretic and immunological characteristics of
which are similar to those of a recombinant rabbit GHR mutant that
lacks the extracellular domain, was such that progressively faster
migrating forms were evident between 5–60 min of PMA exposure.
Treatment with N-ethylmaleimide (NEM; 5 mM),
an agent known to cause GHBP shedding from IM-9 cells, promoted a
similar rapid loss of full-length GHRs and an accumulation of GHR
cytoplasmic domain remnant proteins. PMA-induced, but not NEM-induced,
GHR proteolysis was blocked by the protein kinase C inhibitor,
GF109203X. Both PMA- and NEM-induced receptor proteolysis were,
however, inhibited by the metalloprotease inhibitor, Immunex Compound 3
(minimum effective concentration, 10 µM). Notably, PMA
and NEM also promoted shedding of GHBP into the conditioned medium of
the cells, as determined by a chromatographic [125I]human
GH binding assay; this GHBP shedding was also inhibited by Immunex
Compound 3. These results strongly implicate a member(s) of the
metalloprotease family as a potential GHBP-generating enzyme.
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R. Guan, Y. Zhang, J. Jiang, C. A. Baumann, R. A. Black, G. Baumann, and S. J. Frank Phorbol Ester- and Growth Factor-Induced Growth Hormone (GH) Receptor Proteolysis and GH-Binding Protein Shedding: Relationship to GH Receptor Down-Regulation Endocrinology, March 1, 2001; 142(3): 1137 - 1147. [Abstract] [Full Text] [PDF]
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Y. Zhang, J. Jiang, J. J. Kopchick, and S. J. Frank Disulfide Linkage of Growth Hormone (GH) Receptors (GHR) Reflects GH-induced GHR Dimerization. ASSOCIATION OF JAK2 WITH THE GHR IS ENHANCED BY RECEPTOR DIMERIZATION J. Biol. Chem., November 12, 1999; 274(46): 33072 - 33084. [Abstract] [Full Text] [PDF]
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 C. L. Chaffin and R. L. Stouffer Expression of Matrix Metalloproteinases and Their Tissue Inhibitor Messenger Ribonucleic Acids in Macaque Periovulatory Granulosa Cells: Time Course and Steroid Regulation Biol Reprod, July 1, 1999; 61(1): 14 - 21. [Abstract] [Full Text]
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T. Amit, O. Bar-Am, F. Dastot, M. B. H. Youdim, S. Amselem, and Z.'e. Hochberg The Human Growth Hormone (GH) Receptor and Its Truncated Isoform: Sulfhydryl Group Inactivation in the Study of Receptor Internalization and GH-Binding Protein Generation Endocrinology, January 1, 1999; 140(1): 266 - 272. [Abstract] [Full Text]
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Y. Zhang, R. Guan, J. Jiang, J. J. Kopchick, R. A. Black, G. Baumann, and S. J. Frank Growth Hormone (GH)-induced Dimerization Inhibits Phorbol Ester-stimulated GH Receptor Proteolysis J. Biol. Chem., June 29, 2001; 276(27): 24565 - 24573. [Abstract] [Full Text] [PDF]
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