The pituitary hormones growth hormone (GH), prolactin (PRL) and placental lactogen (PL), are members of an extensive cytokine superfamily of hormones and receptors that share many of the same general structure-function relationships in expressing their biological activities. The biology of the pituitary hormones involves a very sophisticated interplay of cross-reactivity and specificity. Biological activity is triggered via a hormone-induced receptor homodimerization process that is regulated by tertiary features of the hormone. These hormones have an asymmetric four a-helical bundle structure that gives rise to two receptor binding sites that have distinctly different topographies and electrostatic character. This feature plays an important role in the regulation of these systems by producing binding surfaces with dramatically different binding affinities to the receptor extracellular domains (ECD). As a consequence, the signaling complexes for systems that activate through receptor homo-dimerization are formed in a controlled sequential step-wise manner. Extensive biochemical and biophysical characterization of the two hormone-receptor interfaces indicate that the energetic properties of the two binding sites are fundamentally different and that the receptor shows extraordinary conformational plasticity to mate with the topographically dissimilar sites on the hormone. An unexpected finding has been that the two hormone binding sites are allosterically coupled; a certain set of mutations in the higher affinity site can produce both conformational and energetic effects in the lower affinity site. These effects are so large that at some level they must have played some role in the evolution of the molecule. Prolactin (PRL), placental lactogen (PL) and growth hormone (GH) are pituitary hormones that regulate an extensive variety of important physiological functions. The biology of prolactin and growth hormone is integrated on many levels (Goffin et al., 1996); however, over the 400 million years since they diverged from a common gene parent, evolution has built in different regulating components distinguishing them (Gertler et al., 1996; Nicoll et al., 1986). While growth hormone biology generally centers around the regulation and differentiation of muscle, cartilage, and bone cells, it is the prolactin hormones and receptors that display a much broader spectrum of activities ranging in diversity from their well known effects in mammalian reproductive biology to osmoregulation in fishes and nesting behavior in birds (DeVlaming, 1979). The endocrine activities of prolactin and growth hormone are triggered by hormone-induced homodimerization of their cognate receptors. The receptors belong to the large hematopoietic receptor superfamily (Bazan, 1990; Cosman et al., 1990). In primates, the growth hormone receptor (GHR) is activated solely by homodimerization through binding to growth hormone (De Vos et al., 1992; Nicoll et al., 1986). However, prolactin biology works through regulated cross-reactivity; most receptors are programmed to bind three hormones: prolactin (PRL), placental lactogen (PL), and growth hormone (GH) (Kelly et al., 1991). Additionally, there is a set of activities that are induced by post-translational modified forms of prolactin that probably react through a non-cytokine type of receptor (Sinha, 1995). The GHR and PRLR receptors have a three-domain organization: (1) an extracellular domain, which binds the activating hormone and is responsible for conferring specificity; (2) a short transmembrane a-helix segment (similar to25 residues); and (3) a cytoplasmic domain. While most of the receptors in the superfamily contain some number of FNIII domains in their extracellular portion and have a similar length transmembrane segment, their cytoplasmic portions generally have little similarity. Interestingly, it is the cytoplasmic portion that is the target for the JAK tyrosine kinases that trans-phosphorylate elements on themselves, the receptors and associated transcription factors, which leads to the first steps in signal transduction (Ihle et al., 1994). Within the cytokine super family, the growth hormone (GH)/prolactin (PRL) family of hormones and receptors are arguably the most extensively studied systems focused on structure-function issues and molecular recognition (Bazan, 1990; De Vos and Kossiakoff, 1992; Kossiakoff and De Vos, 1998; Kossiakoff et aL, 1994; Sprang and Bazan, 1993; Wells, 1991; Wells and De Vos, 1996). These studies and those of related cytokine systems have been instrumental in defining modes of hormone action and regulation (Banner et aL, 1996; De Vos el aL, 1992; Somers et aL, 1994; Syed et aL, 1998; Walter et aL, 1995; Wiesmann et aL, 1997). The structure-based mechanisms by which these systems activate are similar (Banner el aL, 1996; Sprang and Bazan, 1993; Wells and De Vos, 1996). However, although these mechanisms are conceptually simple-hormone induced receptor aggregation (Fig. 1)-the molecular strategies that are employed are complex and hardly predictable (Atwell el al., 1997; De Vos et al., 1992; Kossiakoff et al., 1994; Somers et al., 1994).
