THE GROWTH-HORMONE BINDING-PROTEIN AS A PARADIGM OF THE ERYTHROPOIETIN SUPERFAMILY OF RECEPTORS

The growth hormone (GH) receptor belongs to a novel receptor family which shares significant amino-acid sequence homology and includes prolactin receptors, erythropoietin receptors and several cytokines' receptors. GH and three other members of this family of receptors have been shown to have circulating soluble forms. The present review summarizes our knowledge on receptor related binding proteins, discusses their possible biological effects and suggests their use in novel assays for their ligands. The GH-binding protein (GH-BP) was the first to have been described and is used as a model for the concept. A series of indirect pieces of evidence suggest that the measurement of circulating GH-BP may enable an evaluation of the GH-receptor. When covalently bound to GH, GH-BP has been shown to slow the clearance of GH. On the other hand GH-BP competes with the GH-receptor for GH binding and, thus, diminishes the biological effect of GH. We suggest a biological role for GH-BP as follows: an increase in the availability of GH results not only in the up-regulation of the GH-receptor but also in increased turnover of this receptor, its internalization and recycling. This is followed by a concomitant increase in GH-BP which, in turn, mitigates the effect of GH by competing with the receptor on GH binding. The extracellular domain of the GH-receptor is homologous, to a large extent, with the sequence of several receptors for hormones and cytokines, which have recently been cloned. Comparing their sequences with a library of consensus sequences, it was found that the C terminal part of the extracellular domains of the new receptor family contains a domain found in several proteins mediating protein-protein interactions. The functional significance of the soluble circulating forms of this new receptor family has yet to be studied. The availability of soluble forms of receptor (binding proteins) may unveil a family of novel assays for hormones and cytokines. A binding protein based assay will use the advantages and egest the disadvantages of the RIA and RRA.