Stuart N. Behncken

Growth hormone as a cytokine

1. The growth hormone (GH) receptor was the first of the class 1 cytokine receptors to be cloned. It shares a number of structural characteristics with other family members and common signalling mechanisms based on common usage of the Janus kinase 2 (JAK2).

Aspartate 171 Is the Major Primate-specific Determinant of Human Growth Hormone ENGINEERING PORCINE GROWTH HORMONE TO ACTIVATE THE HUMAN RECEPTOR

It has been known for more than 4 decades that only primate growth hormones are effective in primate species, but it is only with the availability of the 2.8 Å structure of the human growth hormone (hGH)·hGH-binding protein (hGHBP)2complex that Souza and co-workers (Souza, S. C., Frick, G. P., Wang, X., Kopchick, J. J., Lobo, R. B., and Goodman, H. M. (1995)Proc. Natl. Acad. Sci. U. S. A. 92, 959–963) were able to provide evidence that Arg-43 on the primate receptor is responsible. Here we have examined systematically the interaction between Arg-43 (primate receptor) or Leu-43 (non-primate receptors) and their complementary hormone residues Asp-171 (primate GH) and His-170 (non-primate hormones) in a four-way comparison involving exchanges of histidine and aspartate and exchanges of arginine and leucine. BAF/B03 lines were created and characterized which stably expressed hGH receptor, R43L hGH receptor, rabbit GH receptor, and L43R rabbit GH receptor. These were examined for site 1 affinity, for the ability to bind intact cells, and for proliferative biopotency using hGH, D171H hGH, porcine GH, or H170D porcine GH. We find that the single interaction between Arg-43 and His-170/171 is sufficient to explain virtually all of the primate species specificity, and this is congruent with the crystal structure. Accordingly, for the first time we have been able to engineer a non-primate hormone to bind to and activate the human GH receptor.

Molecular recognition events involved in the activation of the growth hormone receptor by growth hormone

Binding of growth hormone (GH) to its receptor (GHR) is a well‐studied example of molecular recognition between a cytokine and its receptor. Extensive mutagenesis studies and several crystal structures have defined the key interactive amino acid residues that are involved in binding and subsequent receptor dimerization. This review encompasses each of the three molecular recognition events involved in GHR activation, namely binding of GH to its two receptors and the interactions that occur between these receptors. Particular attention is given to species and ligand specificity of hormone binding and to the molecular recognition events involved in receptor activation, including the possibility that a conformational change in the receptor is required. Copyright

Prospects for a small molecule able to induce somatic growth through the growth hormone receptor

This article reviews the prospects for a small-molecule agonist of the growth hormone receptor in the light of current successes in identifying small agonist molecules for other homomeric class 1 cytokine receptors. A variety of mutagenic analyses on both hormone and receptor, studies with monoclonal antibody agonists of the GH receptor, and the use of a constitutively dimerized GH receptor chimera which displays constitutive activity lead us to believe that such a development is possible. However, it is likely that a precise alignment of the lower cytokine receptor homology domains will be necessary in order to facilitate cross-activation of cytoplasmic Janus kinases bound to Box 1.