Prolactin Signaling

Prolactin (Prl) is a multifunctional hormone secreted by the anterior pituitary gland, involved in more than 300 separate effects. These can be ascribed to six broad categories: reproduction and lactation, growth and development, endocrinology and metabolism, brain and behaviour, immunomodulation and osmoregulation. Prl acts as a pleiotropic cytokine promoting cellular proliferation and differentiation of a variety of cell types. It activates a mitogenic signaling pathway with a concurrent gain in differentiation. The best known cascades involve the JAK-STAT pathway, the Ras-Raf-MAPK pathway, the Src tyrosine kinases and PLC-γ.Prl exerts its effects at the molecular level by inducing the homodimmerization of Prl. Two protein tyrosine kinases found in association with the PrlR are Fyn and JAK2. Through JAK2, Prl stimulation recruits and activates the STAT family of transcription factors, in particular STAT1, STAT3 and STAT5 resulting in the initiation of transcription of IRF1 and β-casein gene products. The phosphorylated STAT proteins dimerize, translocate to the nucleus, and bind to specific DNA sequences in the promoters of Prl induced genes, activating gene transcription. STAT5 interacts with steroid receptors like GR, the co-activator CBP/p300, NMI protein and ERK1/2. Intranuclear STAT5 binds to consensus STAT5 response elements, resulting in the transactivation of numerous Prl specific genes including β-casein. This STAT5 transcriptional activation can be cooperatively enhanced by GR and CEBPβ. The gene promoters of both cyclin-D1 (which regulates cell-cycle progression) and the antiapoptotic factor Bcl-X are targeted by STAT5 proteins.PrlR dimerization also induces the GRB2-SOS-Ras-Raf-MEK-MAPK signaling cascade, ultimately activating several transcription factors necessary for cell cycle progression including Myc, c-Jun, and TCF. In addition, PLC-PKC and PI3K are also effectors of PrlR. PI3K activates the Akt/PKB pathway that ultimately contributes to cell survival. Numerous other proteins become tyrosine phosphorylated following activation of the PrlR, including the receptor itself, the SH2 containing adapter protein SHC, and IRS1. The SH2 domain containing SHP2 contributes to PrlR activation of β-casein. In immune cells, Prl induces the expression of an immediate early gene, IRF1, which regulates the expression of genes associated with the immune response. A number of mediators positively regulate Prl stimulation of IRF1 gene transcription. These include Prlinducible STAT1, the constitutive factor SP1, and the coactivator p300/CBP which enhances STAT1 activation of the IRF1 promoter.The SOCS proteins contribute to down regulation of Prl signal transduction. Constitutive expression of SOCS1 and SOCS3 suppress Prl induced STAT5 dependent gene transcription and Jak2 tyrosine kinase activity is greatly reduced in the presence of SOCS1 or SOCS3, whereas SOCS2 is associated with the PrlR. The ability of Prl to act both as a survival (antiapoptotic) factor and as a mitogen has been associated with a number of different forms of cancer. It is also suggested that Prl isinvolved in the etiology of cystic fibrosis. Since hyperprolactinemia and hypoprolactinemia are both immunosuppressive, optimum physiological levels of circulating Prl are necessary to maintain basal immunocompetence. In humans, hyperprolactinemia is associated with amenorrhea, galactorrhea and impotence. The inhibitory effects on the reproductive processes may be due to both central and peripheral actions of Prl. In some women, elevated Prl is associated with a psychosomatic state of pseudo pregnancy.