Prolactin Signaling
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Prolactin Signaling
Prl (Prolactin), a multifunctional hormone secreted by the anterior pituitary gland and to a lesser extent by numerous extrapituitary tissues, affects more physiological processes than all other pituitary hormones combined. It was originally identified by its ability to stimulate the development of the mammary gland and lactation. However, this hormone has been established to be present in all vertebrates, and involved in more than 300 separate effects (Ref.1), which can be ascribed to six broad categories: (i) reproduction and lactation, (ii) growth and development, (iii) endocrinology and metabolism, (iv) brain and behaviour, (v) immunomodulation and (vi) osmoregulation (Ref.2). It acts as a pleiotropic cytokine promoting cellular proliferation and differentiation of a variety of cell types (Ref.3).

Prl activates a mitogenic signaling pathway with a concurrent gain in differentiation. The initial step in its action is the binding to a specific membrane receptor referred to as PrlR (Prolactin Receptor) which belongs to the superfamily of class 1 cytokine receptors (Ref.1). The PrlR comprises a single transmembrane region that divides the receptor into an extracellular ligand-binding domain and an intracellular domain. The extracellular domain has two disulfide bonds and a Trp-Ser-X-Trp-Ser motif. The cytoplasmic domain has a proline-rich motif that couples to protein kinase signaling molecules. The PrlR, like the other members of this family, does not contain a tyrosine kinase domain but signals through activation of associated cytoplasmic tyrosine kinases of the JAK (Janus Kinase) family and SFKs (Src Family Of Tyrosine Kinases) which in turn activate downstream effectors. The main and best-known cascades involve the JAK-STAT pathway, the Ras-Raf-MAPK pathway, the Src tyrosine kinases and PLC-Gamma (Phospholipase-C-Gamma) (Ref.4).

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 STAT (Signal Transducers and Activators Of Transcription) family of transcription factors, in particular STAT1, STAT3 and STAT5, in lymphocytes and other cells, resulting in the initiation of transcription for IRF1 (Interferon Regulatory Factor-1) and Beta-Casein gene products, respectively. The STATs are considered as major effectors for Prl-dependent cell proliferation and gene activation, with STATs 5A and 5B serving as the primary mediators. The phosphorylated STAT proteins dimmerize, translocate to the nucleus, and bind to specific DNA sequences in the promoters of Prl-induced genes, activating gene transcription (Ref.4). STAT5 interacts with steroid receptors like the GR (Glucocorticoid Receptor), the co-activator CBP (CREB Binding Protein)/p300, NMI (N-Myc [and STAT] Interactor) protein and ERK1/2 (Extracellular Signal Regulated Kinases). Intranuclear STAT5 binds to consensus STAT5 response elements, resulting in the transactivation of numerous Prl-specific genes including Beta-casein. This STAT5 transcriptional activation can be cooperatively enhanced by the GR and CEBPBeta (CCAAT/Enhancer Binding Protein-Beta). The gene promoters of both Cyclin-D1 (which regulates cell-cycle progression) and the antiapoptotic factor BclXL are targeted by STAT5 proteins (Ref.5).

PrlR dimmerization 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 (T-Cell Factor). In addition, PLC-PKC (Protein Kinase-C) and PI3K (Phosphatidylinositol 3-Kinase) activation have also been reported as effectors of PrlR. PI3K further 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 the IRS1 (Insulin Receptor Substrate-1) (Ref.4). The SH2 (Src Homology-2) domain containing protein-tyrosine phosphatase SHP2 contributes to PrlR signal transduction to Beta-Casein gene promoter activation. SHP2 physically associates with STAT5A and is critical for the activation of the STAT5 GAS (IFN-Gamma-Activated Sequence) element of Beta-Casein gene promoter (Ref.5). Beta-Casein gene transcription is controlled primarily by CoRE (Composite Response Element). In immune cells, Prl induces the expression of an immediate early gene, the IRF1, which regulates the expression of IL-2 (Interleukin-2), IFNs (Interferons), IFN-induced genes and other genes associated with immune response. IRF1 promoter contains one critical GAS element. A number of mediators positively regulate Prl stimulation of IRF1 gene transcription. These include Prl-inducible STAT1, the constitutive factor SP1 (Transcription Factor SP1), and the coactivator p300/CBP (CREB Binding Protein), which enhances STAT1 activation of the IRF1 promoter. Prl-inducible STAT5 inhibits IRF1 transcription (Ref.6).

The SOCS (Suppressor of Cytokine Signaling) gene family has been identified as targets of the JAK-STAT pathway that 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 (Ref.7). Carcinogenesis results from a progressive loss of cellular control mechanisms and is affected by genetic, environmental, dietary and hormonal factors. 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. For example, Both Prl and PrlR mRNA are expressed in the vast majority of breast cancer biopsies. Further, Prl function is attributed to increase colorectal tumor agressivity, induce the proliferation of several lines of human breast cancer, activate malignant B-lymphocytes and lymphoma cells, and induce the proliferation of promyelocytes. Benign fibromuscular myometrial tumors (leiomyomas) have been shown to produce Prl in large quantities. Establishment of Prl as an active participant in tumorigenesis should inspire the development of novel therapies aimed at reducing tumor growth by suppressing Prl production or by blocking its receptors. Prl has been shown to be increased and to effect a number of autoimmune states, such as systemic lupus erythematosus, acute allergic encephalomyelitis, rheumatoid arthritis, adjuvant arthritis, and graft vs. host disease. Prl is also suggested to be involved 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 has been shown to be 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 pseudopregnancy (Ref.8).