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Prolactin (PRL) and growth hormone (GH)2 receptors are members of the cytokine receptor superfamily that are activated by ligand-induced homodimerization. On the basis of this mechanism of activation, hormone antagonists have been developed that block the receptors in an inactive conformation. PRL and GH receptors are non-kinase receptors whose activation of signaling pathways requires participation of receptor-associated kinases, such as Janus kinases or Src kinases. Signal transduction by these receptors mainly involves the JAK/Stat pathway. In this review, we discuss the mechanism of ligand binding and receptor homodimerization as well as the involvement of molecules transducing the hormonal signal. Whenever possible, we attempt to correlate cytoplasmic features of the receptors with association and/ or activation of transducer molecules or with a given biological property.
KEY WORDS: Prolactin; growth hormone; cytokine; receptor; dimerization; JAK; Stat.
INTRODUCTION
Prolactin (PRL; Fig. 1) and growth hormone (GH) are secreted by the pituitary and exert a wide spectrum of biological effects mainly related to reproduction, lactation, growth, and metabolism. These bioactivities are initiated by the interaction of the hormones with specific membrane receptors (R) found in their numerous target tissues. Within the last ten years, the understanding of PRL and GH functions at the physiological level has made major advances due to several discoveries at the molecular level, the first of which was the cloning of the cDNAs encoding their respective receptors. The aim of this review is to describe the most recent progress on the structure/function relationships of both PRLR and GHR. Our discussion thus encompasses the overall series of events beginning at the cell surface, involving the interaction of hormones with the extracellular domain of receptors, to events occurring inside the cell, including the molecules that participate in the transduction of the hormonal message from the membrane to the nucleus.
CYTOKINE RECEPTOR SUPERFAMILY
Both PRLR and GHR are single chain proteins with a single transmembrane domain (Fig. 2). The cDNA encoding the human (h)GHR was cloned in 1987 and encodes a mature protein composed of 620 amino acids (aa), divided into an extracellular (246 aa), a transmembrane (24 aa) and a cytoplasmic (350 aa) domain. The first cloned PRLR was isolated from a rat liver cDNA library and encodes a much smaller protein (291 aa) with...