Prolactin receptor signaling (Homo sapiens)

Jump to: navigation, search

Prolactin (PRL) is a hormone secreted mainly by the anterior pituitary gland. It was originally identified by its ability to stimulate the development of the mammary gland and lactation, but is now known to have numerous and varied functions (Bole-Feysot et al. 1998). Despite this, few pathologies have been associated with abnormalities in prolactin receptor (PRLR) signaling, though roles in various forms of cancer and certain autoimmune disorders have been suggested (Goffin et al. 2002). A vast body of literature suggests effects of PRL in immune cells (Matera 1996) but PRLR KO mice have unaltered immune system development and function (Bouchard et al. 1999). In addition to the pituitary, numerous other tissues produce PRL, including the decidua and myometrium, certain cells of the immune system, brain, skin and exocrine glands such as the mammary, sweat and lacrimal glands (Ben-Jonathan et al. 1996). Pituitary PRL secretion is negatively regulated by inhibitory factors originating from the hypothalamus, the most important of which is dopamine, acting through the D2 subclass of dopamine receptors present in lactotrophs (Freeman et al. 2000). PRL-binding sites or receptors have been identified in numerous cells and tissues of adult mammals. Various forms of PRLR, generated by alternative splicing, have been reported in several species including humans (Kelly et al. 1991, Clevenger et al. 2003).

PRLR is a member of the cytokine receptor superfamily. Like many other members of this family, the first step in receptor activation was generally believed to be ligand-induced dimerization whereby one molecule of PRL bound to two molecules of receptor (Elkins et al. 2000). Recent reports suggest that PRLR pre-assembles at the plasma membrane in the absence of ligand (Gadd & Clevenger 2006, Tallet et al. 2011), suggesting that ligand-induced activation involves conformational changes in preformed PRLR dimers (Broutin et al. 2010).

PRLR has no intrinsic kinase activity but associates (Lebrun et al. 1994, 1995) with Janus kinase 2 (JAK2) which is activated following receptor activation (Campbell et al. 1994, Rui et al. 1994, Carter-Su et al. 2000, Barua et al. 2009). JAK2-dependent activation of JAK1 has also been reported (Neilson et al. 2007). It is generally accepted that activation of JAK2 occurs by transphosphorylation upon ligand-induced receptor activation, based on JAK activation by chimeric receptors in which various extracellular domains of cytokine or tyrosine kinase receptors were fused to the IL-2 receptor beta chain (see Ihle et al. 1994). This activation step involves the tyrosine phosphorylation of JAK2, which in turn phosphorylates PRLR on specific intracellular tyrosine residues leading to STAT5 recruitment and signaling, considered to be the most important signaling cascade for PRLR. STAT1 and STAT3 activation have also been reported (DaSilva et al. 1996) as have many other signaling pathways; signaling through MAP kinases (Shc/SOS/Grb2/Ras/Raf/MAPK) has been reported as a consequence of PRL stimuilation in many different cellular systems (see Bole-Feysot et al. 1998) though it is not clear how this signal is propagated. Other cascades non exhaustively include Src kinases, Focal adhesion kinase, phospholipase C gamma, PI3 kinase/Akt and Nek3 (Clevenger et al. 2003, Miller et al. 2007). The protein tyrosine phosphatase SHP2 is recruited to the C terminal tyrosine of PRLR and may have a regulatory role (Ali & Ali 2000). PRLR phosphotyrosines can recruit insulin receptor substrates (IRS) and other adaptor proteins to the receptor complex (Bole-Feysot et al. 1998).

Female homozygous PRLR knockout mice are completely infertile and show a lack of mammary development (Ormandy et al. 1997). Hemizogotes are unable to lactate following their first pregnancy and depending on the genetic background, this phenotype can persist through subsequent pregnancies (Kelly et al. 2001). Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1170546