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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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Endocrinology 142, 767-777
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H. K. Choi and D. J. Waxman (2000)
Endocrinology 141, 3245-3255
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Designing Small-Molecule Switches for Protein-Protein Interactions.
Z. Guo, D. Zhou, and P. G. Schultz (2000)
Science 288, 2042-2045
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Growth Hormone (GH)-independent Dimerization of GH Receptor by a Leucine Zipper Results in Constitutive Activation.
S. N. Behncken, N. Billestrup, R. Brown, J. Amstrup, B. Conway-Campbell, and M. J. Waters (2000)
J. Biol. Chem. 275, 17000-17007
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Treatment of Acromegaly with the Growth Hormone-Receptor Antagonist Pegvisomant.
P. J. Trainer, W. M. Drake, L. Katznelson, P. U. Freda, V. Herman-Bonert, A.J. van der Lely, E. V. Dimaraki, P. M. Stewart, K. E. Friend, M. L. Vance, et al. (2000)
N. Engl. J. Med. 342, 1171-1177
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Y. Zhang, J. Jiang, J. J. Kopchick, and S. J. Frank (1999)
J. Biol. Chem. 274, 33072-33084
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W. Y. Chen, P. Ramamoorthy, N.-y. Chen, R. Sticca, and T. E. Wagner (1999)
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Mimicry of erythropoietin by a nonpeptide molecule.
S. A. Qureshi, R. M. Kim, Z. Konteatis, D. E. Biazzo, H. Motamedi, R. Rodrigues, J. A. Boice, J. R. Calaycay, M. A. Bednarek, P. Griffin, et al. (1999)
PNAS 96, 12156-12161
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Biological Properties of Human Prolactin Analogs Depend Not Only on Global Hormone Affinity, but Also on the Relative Affinities of Both Receptor Binding Sites.
S. Kinet, S. Bernichtein, P. A. Kelly, J. A. Martial, and V. Goffin (1999)
J. Biol. Chem. 274, 26033-26043
   Abstract »    Full Text »    PDF »
The 20-Kilodalton (kDa) Human Growth Hormone (hGH) Differs from the 22-kDa hGH in the Effect on the Human Prolactin Receptor.
B. Tsunekawa, M. Wada, M. Ikeda, H. Uchida, N. Naito, and M. Honjo (1999)
Endocrinology 140, 3909-3918
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Studies with a Growth Hormone Antagonist and Dual-fluorescent Confocal Microscopy Demonstrate that the Full-length Human Growth Hormone Receptor, but Not the Truncated Isoform, Is Very Rapidly Internalized Independent of Jak2-Stat5 Signaling.
M. Maamra, J. Finidori, S. Von Laue, S. Simon, S. Justice, J. Webster, S. Dower, and R. Ross (1999)
J. Biol. Chem. 274, 14791-14798
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R. Assandri, M. Egger, M. Gassmann, E. Niggli, C. Bauer, I. Forster, and A. Gorlach (1999)
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A. Herman, D. Helman, O. Livnah, and A. Gertler (1999)
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Down-Regulation of Liver JAK2-STAT5b Signaling by the Female Plasma Pattern of Continuous Growth Hormone Stimulation.
C. A. Gebert, S.-H. Park, and D. J. Waxman (1999)
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J. Biol. Chem. 274, 2672-2681
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E Juarez-Aguilar, F Castro-Munozledo, N. Guerra-Rodriguez, D Resendez-Perez, H. Martinez-Rodriguez, H. Barrera-Saldana, and W Kuri-Harcuch (1999)
J. Cell Sci. 112, 3127-3135
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Interaction affinity between cytokine receptor components on the cell surface.
A. Whitty, N. Raskin, D. L. Olson, C. W. Borysenko, C. M. Ambrose, C. D. Benjamin, and L. C. Burkly (1998)
PNAS 95, 13165-13170
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An Agonist Murine Monoclonal Antibody to the Human c-Mpl Receptor Stimulates Megakaryocytopoiesis.
B. Deng, N. Banu, B. Malloy, P. Hass, J. F. Wang, L. Cavacini, D. Eaton, and H. Avraham (1998)
Blood 92, 1981-1988
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Growth Hormone and Insulin-Like Growth Factor I Induce Bone Morphogenetic Proteins 2 and 4: A Mediator Role in Bone and Tooth Formation?.
H. Li, P. M. Bartold, C. Z. Zhang, R. W. Clarkson, W. G. Young, and M. J. Waters (1998)
Endocrinology 139, 3855-3862
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Grb10 Identified as a Potential Regulator of Growth Hormone (GH) Signaling by Cloning of GH Receptor Target Proteins.
S. Moutoussamy, F. Renaudie, F. Lago, P. A. Kelly, and J. Finidori (1998)
J. Biol. Chem. 273, 15906-15912
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Novel Recombinant Analogues of Bovine Placental Lactogen. G133K AND G133R PROVIDE A TOOL TO UNDERSTAND THE DIFFERENCE BETWEEN THE ACTION OF PROLACTIN AND GROWTH HORMONE RECEPTORS.
D. Helman, N. R. Staten, J. Grosclaude, N. Daniel, C. Nespoulous, J. Djiane, and A. Gertler (1998)
J. Biol. Chem. 273, 16067-16074
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Requirements for Binding and Signaling of the Kinase Domain Receptor for Vascular Endothelial Growth Factor.
G. Fuh, B. Li, C. Crowley, B. Cunningham, and J. A. Wells (1998)
J. Biol. Chem. 273, 11197-11204
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Growth Hormone Stimulates the Tyrosine Phosphorylation and Association of p125 Focal Adhesion Kinase (FAK) with JAK2. FAK IS NOT REQUIRED FOR STAT-MEDIATED TRANSCRIPTION.
T. Zhu, E. L. K. Goh, and P. E. Lobie (1998)
J. Biol. Chem. 273, 10682-10689
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An antagonistic vascular endothelial growth factor (VEGF) variant inhibits VEGF-stimulated receptor autophosphorylation and proliferation of human endothelial cells.
G. Siemeister, M. Schirner, P. Reusch, B. Barleon, D. Marme, and G. Martiny-Baron (1998)
PNAS 95, 4625-4629
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Activation of Chimeric and Full-length Growth Hormone Receptors by Growth Hormone Receptor Monoclonal Antibodies. A SPECIFIC CONFORMATIONAL CHANGE MAY BE REQUIRED FOR FULL-LENGTH RECEPTOR SIGNALING.
S. W. Rowlinson, S. N. Behncken, J. E. Rowland, R. W. Clarkson, C. J. Strasburger, Z. Wu, W. Baumbach, and M. J. Waters (1998)
J. Biol. Chem. 273, 5307-5314
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Activation of the Signal Transducers and Activators of Transcription Signaling Pathway by Growth Hormone (GH) in Skin Fibroblasts from Normal and GH Binding Protein-Positive Laron Syndrome Children.
J. S. Freeth, C. M. Silva, A. J. Whatmore, and P. E. Clayton (1998)
Endocrinology 139, 20-28
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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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Stimulation of Mitochondrial Fatty Acid Oxidation by Growth Hormone in Human Fibroblasts.
K.-C. Leung and K. K. Y. Ho (1997)
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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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S. N. Behncken, S. W. Rowlinson, J. E. Rowland, B. L. Conway-Campbell, T. A. Monks, and M. J. Waters (1997)
J. Biol. Chem. 272, 27077-27083
   Abstract »    Full Text »    PDF »
Agonistic and Antagonistic Variants of Ciliary Neurotrophic Factor (CNTF) Reveal Functional Differences between Membrane-bound and Soluble CNTF alpha -Receptor.
A. Di Marco, I. Gloaguen, A. Demartis, I. Saggio, R. Graziani, G. Paonessa, and R. Laufer (1997)
J. Biol. Chem. 272, 23069-23075
   Abstract »    Full Text »    PDF »
Identification of a Motif Associated with the Lactogenic Actions of Human Growth Hormone.
F. C. Peterson and C. L. Brooks (1997)
J. Biol. Chem. 272, 21444-21448
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Functional growth hormone (GH) receptors and GH are expressed by preimplantation mouse embryos: A role for GH in early embryogenesis?.
M. Pantaleon, E. J. Whiteside, M. B. Harvey, R. T. Barnard, M. J. Waters, and P. L. Kaye (1997)
PNAS 94, 5125-5130
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Circulating Non-22-Kilodalton Growth Hormone Isoforms in Acromegalic Men before and after Transsphenoidal Surgery.
C. L. Boguszewski, G. Johannsson, B.-A. Bengtsson, A. Johansson, B. Carlsson, and L. M. S. Carlsson (1997)
J. Clin. Endocrinol. Metab. 82, 1516-1521
   Abstract »    Full Text »    PDF »
Growth Hormone Stimulates the Proliferation of Activated Mouse T Lymphocytes.
M.-C. Postel-Vinay, V. de Mello Coelho, M.-C. Gagnerault, and M. Dardenne (1997)
Endocrinology 138, 1816-1820
   Abstract »    Full Text »    PDF »
The Somatogenic Hormones and Insulin-Like Growth Factor-1: Stimulators of Lymphopoiesis and Immune Function.
R. Clark (1997)
Endocr. Rev. 18, 157-179
   Abstract »    Full Text »
Regulation of Signal Transducer and Activator of Transcription (STAT) 5b Activation by the Temporal Pattern of Growth Hormone Stimulation.
C. A. Gebert, S.-H. Park, and D. J. Waxman (1997)
Mol. Endocrinol. 11, 400-414
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Dissecting the thrombopoietin receptor: Functional elements of the Mpl cytoplasmic domain.
J. G. Drachman and K. Kaushansky (1997)
PNAS 94, 2350-2355
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Kit Receptor Dimerization Is Driven by Bivalent Binding of Stem Cell Factor.
M. A. Lemmon, D. Pinchasi, M. Zhou, I. Lax, and J. Schlessinger (1997)
J. Biol. Chem. 272, 6311-6317
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The Role of Receptor Dimerization Domain Residues in Growth Hormone Signaling.
C. Chen, R. Brinkworth, and M. J. Waters (1997)
J. Biol. Chem. 272, 5133-5140
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Analysis of the Human Interleukin-6/Human Interleukin-6 Receptor Binding Interface at the Amino Acid Level: Proposed Mechanism of Interaction.
M. Kalai, F. A. Montero-Julian, J. Grotzinger, V. Fontaine, P. Vandenbussche, R. Deschuyteneer, A. Wollmer, H. Brailly, and J. Content (1997)
Blood 89, 1319-1333
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Dual Agonistic and Antagonistic Property of Nonpeptide Angiotensin AT1 Ligands: Susceptibility to Receptor Mutations.
S. Perlman, C. M. Costa-Neto, A. A. Miyakawa, H. T. Schambye, S. A. Hjorth, A. C. M. Paiva, R. A. Rivero, W. J. Greenlee, and T. W. Schwartz (1997)
Mol. Pharmacol. 51, 301-311
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Two Peptides Derived from the Nerve Growth Factor Precursor Are Biologically Active.
E. Dicou, B. Pflug, M. Magazin, T. Lehy, D. Djakiew, P. Ferrara, V. Nerriere, and D. Harvie (1997)
J. Cell Biol. 136, 389-398
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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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Real-time Kinetic Measurements of the Interactions between Lactogenic Hormones and Prolactin-Receptor Extracellular Domains from Several Species Support the Model of Hormone-induced Transient Receptor Dimerization.
A. Gertler, J. Grosclaude, C. J. Strasburger, S. Nir, and J. Djiane (1996)
J. Biol. Chem. 271, 24482-24491
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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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Antagonistic Properties of Human Prolactin Analogs That Show Paradoxical Agonistic Activity in the Nb2 Bioassay.
V. Goffin, S. Kinet, F. Ferrag, N. Binart, J. A. Martial, and P. A. Kelly (1996)
J. Biol. Chem. 271, 16573-16579
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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 »


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