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Science 19 June 1992:
Vol. 256. no. 5064, pp. 1677 - 1680
DOI: 10.1126/science.256.5064.1677
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Articles

Rational Design of Potent Antagonists to the Human Growth Hormone Receptor

Germaine Fuh , Brian C. Cunningham , Rikiro Fukunaga , Shigekazu Nagata , David V. Goeddel , and James A. Wells

A hybrid receptor was constructed that contained the extracellular binding domain of the human growth hormone (hGH) receptor linked to the transmembrane and intracellular domains of the murine granulocyte colony-stimulating factor receptor. Addition of hGH to a myeloid leukemia cell line (FDC-P1) that expressed the hybrid receptor caused proliferation of these cells. The mechanism for signal transduction of the hybrid receptor required dimerization because monoclonal antibodies to the hGH receptor were agonists whereas their monovalent fragments were not. Receptor dimerization occurs sequentially—a receptor binds to site 1 on hGH, and then a second receptor molecule binds to site 2 on hGH. On the basis of this sequential mechanism, which may occur in many other cytokine receptors, inactive hGH analogs were designed that were potent antagonists to hGH- induced cell proliferation. Such antagonists could be useful for treating clinical conditions of hGH excess, such as acromegaly.


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H. K. Choi and D. J. Waxman (2000)
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Science 288, 2042-2045
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The 20-Kilodalton (kDa) Human Growth Hormone (hGH) Differs from the 22-kDa hGH in the Complex Formation with Cell Surface hGH Receptor and hGH-Binding Protein Circulating in Human Plasma.
M. Wada, H. Uchida, M. Ikeda, B. Tsunekawa, N. Naito, S. Banba, E. Tanaka, Y. Hashimoto, and M. Honjo (1998)
Mol. Endocrinol. 12, 146-156
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Agonistic monoclonal antibodies against the Met receptor dissect the biological responses to HGF.
M Prat, T Crepaldi, S Pennacchietti, F Bussolino, and P. Comoglio (1998)
J. Cell Sci. 111, 237-247
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Identification of a Ligand-binding Site on the Granulocyte Colony-stimulating Factor Receptor by Molecular Modeling and Mutagenesis.
J. E. Layton, J. Iaria, D. K. Smith, and H. R. Treutlein (1997)
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Identification of a Motif Associated with the Lactogenic Actions of Human Growth Hormone.
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R. Clark (1997)
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Kit Receptor Dimerization Is Driven by Bivalent Binding of Stem Cell Factor.
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Homodimerization of Erythropoietin Receptor by a Bivalent Monoclonal Antibody Triggers Cell Proliferation and Differentiation of Erythroid Precursors.
H. Schneider, W. Chaovapong, D. J. Matthews, C. Karkaria, R. T. Cass, H. Zhan, M. Boyle, T. Lorenzini, S. G. Elliott, and L. B. Giebel (1997)
Blood 89, 473-482
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Mapping of the Active Site of Recombinant Human Erythropoietin.
S. Elliott, T. Lorenzini, D. Chang, J. Barzilay, and E. Delorme (1997)
Blood 89, 493-502
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Crystal Structure of an Antagonist Mutant of Human Growth Hormone, G120R, in Complex with Its Receptor at 2.9AResolution.
M. Sundstrom, T. Lundqvist, J. Rodin, LutzB. Giebel, D. Milligan, and G. Norstedt (1996)
J. Biol. Chem. 271, 32197-32203
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Long-acting Growth Hormones Produced by Conjugation with Polyethylene Glycol.
R. Clark, K. Olson, G. Fuh, M. Marian, D. Mortensen, G. Teshima, S. Chang, H. Chu, V. Mukku, E. Canova-Davis, et al. (1996)
J. Biol. Chem. 271, 21969-21977
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Characterization of Lactogen Receptor-binding Site 1of Human Prolactin.
S. Kinet, V. Goffin, V. Mainfroid, and J. A. Martial (1996)
J. Biol. Chem. 271, 14353-14360
   Abstract »    Full Text »    PDF »
Characterization of the Receptor Binding Sites of Human Leukemia Inhibitory Factor and Creation of Antagonists.
K. R. Hudson, A. B. Vernallis, and J. K. Heath (1996)
J. Biol. Chem. 271, 11971-11978
   Abstract »    Full Text »    PDF »
Growth Hormone (GH) and a GH Antagonist Promote GH Receptor Dimerization and Internalization.
P. A. Harding, X. Wang, S. Okada, W. Y. Chen, W. Wan, and J. J. Kopchick (1996)
J. Biol. Chem. 271, 6708-6712
   Abstract »    Full Text »    PDF »
Short Stature Caused by a Mutant Growth Hormone.
Y. Takahashi, H. Kaji, Y. Okimura, K. Goji, H. Abe, and K. Chihara (1996)
N. Engl. J. Med. 334, 432-436
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Ligand Binding Characteristics of the Carboxyl-terminal Domain of the Cytokine Receptor Homologous Region of the Granulocyte Colony-stimulating Factor Receptor.
H. Anaguchi, O. Hiraoka, K. Yamasaki, S. Naito, and Y. Ota (1995)
J. Biol. Chem. 270, 27845-27851
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Requirement for the Immunoglobulin-like Domain of Granulocyte Colony-stimulating Factor Receptor in Formation of a 2:1 Receptor-Ligand Complex.
O. Hiraoka, H. Anaguchi, A. Asakura, and Y. Ota (1995)
J. Biol. Chem. 270, 25928-25934
   Abstract »    Full Text »    PDF »
A Single Amino Acid Exchange, Arg-45 to Ala, Generates an Epidermal Growth Factor (EGF) Mutant with High Affinity for the Chicken EGF Receptor.
M. L. M. van de Poll, A. E. G. Lenferink, M. J. H. van Vugt, J. J. L. Jacobs, J. W. H. Janssen, M. Joldersma, and E. J. J. van Zoelen (1995)
J. Biol. Chem. 270, 22337-22343
   Abstract »    Full Text »    PDF »
Identification of Phenylalanine 346 in the Rat Growth Hormone Receptor as Being Critical for Ligand-mediated Internalization and Down-regulation.
G. Allevato, N. Billestrup, L. Goujon, E. D. Galsgaard, G. Norstedt, M.-C. Postel-Vinay, P. A. Kelly, and J. H. Nielsen (1995)
J. Biol. Chem. 270, 17210-17214
   Abstract »    Full Text »    PDF »
Prolactin Receptor Antagonists That Inhibit the Growth of Breast Cancer Cell Lines.
G. Fuh and J. A. Wells (1995)
J. Biol. Chem. 270, 13133-13137
   Abstract »    Full Text »    PDF »
Interleukin-6 (IL-6) Antagonism by Soluble IL-6 Receptor [IMAGE] Mutated in the Predicted gp130-binding Interface.
A. L. Salvati, A. Lahm, G. Paonessa, G. Ciliberto, and C. Toniatti (1995)
J. Biol. Chem. 270, 12242-12249
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Species-specific Agonist/Antagonist Activities of Human Interleukin-4 Variants Suggest Distinct Ligand Binding Properties of Human and Murine Common Receptor [IMAGE] Chain.
D. Bönsch, W. Kammer, A. Lischke, and K. Friedrich (1995)
J. Biol. Chem. 270, 8452-8457
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Intracellular Tyrosine Residues of the Human Growth Hormone Receptor Are Not Required for the Signaling of Proliferation or Jak-STAT Activation.
Y.-D. Wang, K. Wong, and W. I. Wood (1995)
J. Biol. Chem. 270, 7021-7024
   Abstract »    Full Text »    PDF »
Ligand-dependent G Protein Coupling Function of Amyloid Transmembrane Precursor.
T. Okamoto, S. Takeda, Y. Murayama, E. Ogata, and I. Nishimoto (1995)
J. Biol. Chem. 270, 4205-4208
   Abstract »    Full Text »    PDF »
Rational Design of a Mouse Granulocyte Macrophage- Colony-stimulating Factor Receptor Antagonist.
S. W. Altmann and R. A. Kastelein (1995)
J. Biol. Chem. 270, 2233-2240
   Abstract »    Full Text »    PDF »
A hot spot of binding energy in a hormone-receptor interface.
T Clackson and J. Wells (1995)
Science 267, 383-386
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