The Prolactin/Growth Hormone Receptor Family

Abstract

PRL and GH are hormones with a wide spectrum of actions. Specific receptors are widely distributed in a number of classical target organs, but other tissues that are not known targets also contain measurable binding sites or receptor mRNA. The most likely explanation is that PRL and GH cause effects that have not yet been characterized in certain tissues. Cloning of the cDNAs encoding PRL and GH receptors has led to the discovery that the receptors, like the hormones themselves, form a gene family. Multiple receptor forms have been identified, including a short form, which for PRL is a membrane-bound receptor or for GH is a soluble BP, and a long form, which for both PRL and GH is a membrane-bound receptor. PRL and GH receptors, and the mRNAs encoding them, can be up- and down-regulated. GH induces an up-regulation of both GH and PRL receptors, whereas PRL stimulates an increase of only its own receptor. High concentrations of either hormone induce a homologous down-regulation of receptor expression. An assay has been developed to measure the functional activity of different forms of PRL receptor by cotransfecting a milk protein fusion gene specific to PRL coupled to a reporter-gene along with the cDNA of the PRL receptor. Although the short form represents the major form present in rat mammary gland, only the long form of receptor is able to stimulate milk protein gene transcription. For GH, increased expression of the receptor in some target cells is accompanied by a modest enhancement of the response to GH. No single second messenger mediating the action of either PRL or GH has been identified. Several potential components of the signal transduction pathways have been identified, but as yet none has clearly been shown to be able to mimic the effect of PRL or GH. Because of the wide range of biological actions associated with PRL, and the existence of various forms of PRL receptors, it is doubtful that one unifying mechanism of action will be found for this hormone. No human or animal model of a genetic defect of the PRL receptor has thus far been published. Mutations in the GH receptor gene have been demonstrated in Laron type dwarfism. Different exon deletions or point or nonsense mutations resulting in modifications in the extracellular, GH binding region of the GH receptor have been reported.(ABSTRACT TRUNCATED AT 400 WORDS)

Basal Testosterone Secretion and Response to Human Luteinizing, Follicle-Stimulating, and Growth Hormones in Culture of Cells Isolated from Testes of Infants and Children

“…PRL binding sites have been described in rat Leydig cells (32). Finally PRL and GH receptor distribution include lymphatic and immune cells (28,33) which are known to be present in the testis. Because hGH has both somatotropic and lactotropic activities (34), it is not possible to discern whether the biologic response detected resulted from an interaction of rhGH with GH or PRL receptors.…”

“…The effect of rhGH was similar to that of hLH and seemed to disappear in cells from older children. Specific receptors for GH and PRL have been described in the testis (28). However, the issue of the presence of GH receptors in the testis is controversial.…”

Human prolactin (hPRL) antagonists inhibit hPRL-activated signaling pathways involved in breast cancer cell proliferation

“…Rather, targeting the activation of the PRLR by using antagonists has emerged as a more reasonable strategy concerning the current state of the art (Go n et al, 1999a). The human PRLR is a member of the cytokine receptor superfamily (Kelly et al, 1991). Its natural ligands are hPRL, placental lactogen (hPL) and, in the presence of zinc, human growth hormone (hGH), which all activate the receptor by inducing its dimerization (Go n et al, 1996a).…”

Feasibility, endocrine and anti-tumour effects of a triple endocrine therapy with tamoxifen, a somatostatin analogue and an antiprolactin in post-menopausal metastatic breast cancer: a randomized study with long-term follow-up

“…The growth effects of both are mediated predominantly via IGF-1 receptors, which have been demonstrated in 67-93% of primary human breast cancers (Pekonen et al, 1988;Peyrat et al, 1988a;Foekens et al, 1989a;Klijn et al, 1993) at higher density than in normal or benign breast tissue (Peyrat et al, 1988b). In vivo, pituitary-derived growth hormone (GH) regulates endocrinologically the secretion of IGF-1 (Kelly et al, 1991;Lamberts et al, 1991), but possibly also has regulatory effects on local IGF-1 secretion within (tumour) tissues (Davoren et al, 1986;Schally et al, 1987;Kelly et al, 1991). In addition, in breast cancer local production of GH with a potential paracrine function has been described (Mol et al, 1995).…”