Probing and Designing Growth Hormone-Receptor Interactions

  • James A. Wells
  • Anthony A. Kossiakoff
Conference paper
Part of the Serono Symposia USA Norwell, Massachusetts book series (SERONOSYMP)


The mechanism through which extracellular signals from hormones trigger intracellular responses is central to understanding how cells and tissues interact. The signaling process is initiated by the binding of polypeptide hormones to cell-surface receptors; however, the molecular basis for binding and receptor activation is not well understood. Through a series of mutational and structural studies, the molecular basis for ligand binding and activation of the growth hormone receptor has been revealed in perhaps greater detail than for any other hormone-receptor system (reviewed in 1–3).


Growth Hormone Human Growth Hormone Growth Hormone Receptor Prolactin Receptor Contact Residue 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Wells J A, De Vos AM. Structure and function of human growth hormone: implications for the hematopoietins. Annu Rev Biophys Biomol Struct 1993; 22: 329–51.PubMedCrossRefGoogle Scholar
  2. 2.
    Wells JA, Cunningham BC, Fuh G, et al. The molecular basis for growth hormone-receptor interactions. Recent Prog Horm Res 1993; 48: 253–75.PubMedGoogle Scholar
  3. 3.
    De Vos AM, Kossiakoff AA. Receptor action and interaction. Curr Opin Struct Biol 1992; 2: 852–8.CrossRefGoogle Scholar
  4. 4.
    Isaksson O, Eden S, Jansson JO. Mode of action of growth hormone on target cells. Annu Rev Physiol 1985; 47: 483–99.PubMedCrossRefGoogle Scholar
  5. 5.
    Leung DW, Spencer SA, Cachianes G, et al. Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature 1987; 330: 537–43.PubMedCrossRefGoogle Scholar
  6. 6.
    Boutin JM, Edrey M, Shirota M, et al. Identification of a cDNA encoding a long form of prolactin receptor in human hepatoma and breast cancer cells. Mol Endocrinol 1989; 3: 1455–61.PubMedCrossRefGoogle Scholar
  7. 7.
    Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA 1990; 87: 6934–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Argetsinger LS, Campbell GS, Yang X, Witthuhn BA, Silvennoinen IJ, Carter-Su C. Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell 1993; 74: 237–44.PubMedCrossRefGoogle Scholar
  9. 9.
    Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990; 61: 203–12.PubMedCrossRefGoogle Scholar
  10. 10.
    Cunningham BC, Ultsch M, De Vos AM, Mulkerrin MG, Clauser KR, Wells JA. Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. Science 1991; 254: 821–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Ultsch M, De Vos AM, Kossiakoff AA. Crystals of the complex between human growth hormone and the extracellular domain of its receptor. J Mol Biol 1991; 222: 865–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Cunningham BC, Jhurani P, Ng P, Wells J A. Receptor and antibody epitopes in human growth hormone identified by homolog-scanning mutagenesis. Science 1989; 243: 1330–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Cunningham BC, Wells JA. High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science 1989; 244: 1081–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Bass SH, Mulkerrin MG, Wells JA. A systematic mutational analysis of hormone-binding determinants in the human growth hormone receptor. Proc Natl Acad Sci USA 1991; 88: 4498–502.PubMedCrossRefGoogle Scholar
  15. 15.
    De Vos AM, Ultsch M, Kossiakoff AA. Human growth hormone and extra-cellular domain of its receptor: crystal structure of the complex. Science 1992; 255: 306–12.PubMedCrossRefGoogle Scholar
  16. 16.
    Cunningham BC, Wells JA. Rational design of receptor-specific variants of human growth hormone. Proc Natl Acad Sci USA 1991; 88: 3407–11.PubMedCrossRefGoogle Scholar
  17. 17.
    Cunningham BC, Bass S, Fuh G, Wells JA. Zinc mediation of the binding of human growth hormone to the human prolactin receptor. Science 1990; 250: 1709–12.PubMedCrossRefGoogle Scholar
  18. 18.
    Cunningham BC, Wells JA. Comparison of a structural and functional epitope. J Mol Biol 1993; 233: 554–63.CrossRefGoogle Scholar
  19. 19.
    Fuh G, Cunningham BC, Fukunaga R, Nagata S, Goeddel DV, Wells JA. Rational design of potent antagonists to the human growth hormone receptor. Science 1992; 256: 1677–80.PubMedCrossRefGoogle Scholar
  20. 20.
    Elberg G, Kelly PA, Djiane J, Binder L, Gertler A. Mitogenic and binding properties of monoclonal antibodies to the prolactin receptor in Nb2 rat lymphoma cells: selective enhancement by anti-mouse IgG. J Biol Chem 1990; 265: 14770–6.PubMedGoogle Scholar
  21. 21.
    Fuh G, Colosi P, Wood WI, Wells JA. Mechanism-based design of prolactin receptor antagonists. J Biol Chem 1993; 268: 5376–81.PubMedGoogle Scholar
  22. 22.
    Silva CM, Weber MJ, Thorner MJ. Stimulation of tyrosine phosphorylation in human cells by activation of the growth hormone receptor. Endocrinology 1992; 132: 101–8.CrossRefGoogle Scholar
  23. 23.
    Ilondo MM, Damholt AB, Cunningham BC, Wells JA, Shymko RM, De Meyts P. Receptor dimerization determines the effects of growth hormone in primary rat adipocytes and cultured human IM-9 lymphocytes. Endocrinology 1994; 134: 2397–403.PubMedCrossRefGoogle Scholar
  24. 24.
    Fu Y-K, Arkins S, Fuh G. Growth hormone augments superoxide anion secretion of human neutrophils by binding to the prolactin receptor. J Clin Invest 1992: 451–7.Google Scholar
  25. 25.
    Feldman M, Ruan W, Cunningham BC, Wells JA, Kleinberg DL. Evidence that the growth hormone receptor mediates differentiation and development of the mammary gland. Endocrinology 1994.Google Scholar
  26. 26.
    Cunningham BC, Henner DJ, Wells JA. Engineering human prolactin to bind to the human growth hormone receptor. Science 1990; 247: 1461–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Lowman HB, Cunningham BC, Wells JA. Mutational analysis and protein engineering of receptor-binding determinants in human placental lactogen. J Biol Chem 1991; 266: 10982–8.PubMedGoogle Scholar
  28. 28.
    Lowman HB, Bass SH, Simpson N, Wells JA. Selecting high-affinity binding proteins by monovalent phage display. Biochemistry 1991; 30: 10832–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Lowman HB, Wells JA. Affinity maturation of human growth hormone by monovalent phage display. J Mol Biol 1993; 234: 564–78.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag New York, Inc. 1995

Authors and Affiliations

  • James A. Wells
  • Anthony A. Kossiakoff

There are no affiliations available

Personalised recommendations