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Abstract

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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Science
Volume 256 | Issue 5064
19 June 1992

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Published in print: 19 June 1992

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Germaine Fuh
Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080.
Brian C. Cunningham
Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080.
Rikiro Fukunaga
Osaka Bioscience Institute, 6-2-4 Furuedai, Suita-shi, Osaka 565, Japan.
Shigekazu Nagata
Osaka Bioscience Institute, 6-2-4 Furuedai, Suita-shi, Osaka 565, Japan.
David V. Goeddel
Department of Molecular Biology, Genentech, Inc., South San Francisco, CA 94080.
James A. Wells
Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080.

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