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Development Prolactin receptor signaling

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Development Prolactin receptor signaling

Prolactin signaling

Prolactin is a polypeptide hormone secreted by the pituitary gland and to alesser extent by numerous extrapituitary tissues. This hormone affects a great amount ofphysiological processes [1]. Numerous biological functions have beenattributed to this hormone's activity, ranging from reproduction and lactation to growthand development, from endocrinology and metabolism to brain and behavior, as well as immune regulation [2]. Prolactin is a primary factor required for thegrowth and terminal differentiation of mammary epithelial cells as determined by theinduction of transcription of milk protein genes required for lactation [2],[3].

The initial step in Prolactin action is the binding to specific membranecytokine receptor, Prolactin receptor [2]. Prolactin receptorhas an extracellular ligand-binding domain and intracellular domain. Prolactin isone of a family of related hormones including growth hormones Somatotropin,Lactogen and CSH1 (somatomammotropin A) that also bind to Prolactinreceptor [4], [5], [6].

The cytoplasmic domain of the Prolactin receptor displays no enzymaticactivity, but signals through activation of associated cytoplasmic tyrosine kinases, suchas Janus kinase 2 (JAK2 ), V-src sarcoma viral oncogene homolog and FYN oncogenerelated to SRC FGR YES ( c-Src and Fyn ), NIMA-related kinase 3 (NEK3 ) and Tec protein tyrosine kinase ( TEC) [7], [8], [9], [10], [11].

JAK2 activity stimulates Prolactin receptor dimerization andphosphorylation. Activated receptor through JAK2 recruits Signal transducers andactivators of transcription (STAT ), in particular STAT1, STAT3 andSTAT5 ( STAT5A and STAT5B ), and stimulates STAT s tyrosinephosphorylation. The phosphorylated STAT s dimmerize and translocate to thenucleus, resulting in the initiation of transcription of Interferon-regulatory factor-1 (IRF-1 ) and milk protein genes (such as Beta-casein andLactoglobulin ) in lymphocytes and mammary gland cells, respectively [12], [13], [14].

In the nucleus STAT s interact with coactivators CBP (CREB bindingprotein), p300, and N-myc interactor (NMI ) [15], [16]. STAT5 transcriptional activation can be cooperatively enhanced by thealpha form of Nuclear receptor subfamily 3 group C member 1 ( GCR-alpha ) andCCAAT/Enhancer binding protein-beta (C/EBPbeta ) to induce the transcription ofBeta-casein gene [17]. Prolactin stimulation of mammary cellsleads to the nuclear translocation of Tyrosine phosphatase non-receptor type 11 (SHP-2 ) as a complex with STAT5A and binding of this complex to DNA,determining the milk protein gene transcription [3], [18].

STAT5 factors also induce the transcription of Cyclin D1 (whichregulates cell cycle progression) and the antiapoptotic factor BCL2-like 1 (Bcl-XL ) [19], [20].

In response to Prolactin receptor stimulation activated STAT stranslocate into the nucleus and bind to the interferon-gamma activation sequence (GAS)in the promoter region of target genes. STAT1 and STAT3 have been shown tostimulate the transcription of the immediate early gene IRF-1 in lymphocytes[21], [22], [23]. STAT1 activation ofIRF-1 promoter is enhanced by the constitutive factor Sp1 transcription factor (SP1 ), and coactivators E1A binding protein p300 ( p300 ) and CREB bindingprotein ( CBP ) [24], [25].

In response to lymphocyte stimulation transcription factors STAT1 and Nuclearfactor kappa B ( NF-kB ) synergistically activate the IRF-1 promoter, viathe GAS and NF-kB elements, respectively [26], [27].STAT5B has been demonstrated to inhibit the IRF-1 transcription, and thisinhibition is dependent upon Prolactin receptor stimulation. STAT5Binhibition does not require binding to the GAS element, but is mediated by squelching oflimiting amounts of p300/ CBP coactivators necessary for genetranscription [28].

In addition, association of 2',5'-oligoadenylate synthetase ( OAS1 ) with theProlactin receptor inhibits STAT1 signaling to the IRF-1 promoter[29].

Suppressors of Cytokine Signaling (SOCS ) gene expression is mediated bySTAT3 and STAT1. SOCS1 and SOCS3 involve in negativeregulation of JAK2 and STAT5 -dependent Beta-casein transcription[30], [31].

Prolactin receptor dimerization also induces the Mitogen-activated proteinkinases pathway via JAK2 and Fyn kinases activation [7],[32], [33]. The complex formations of Fyn/ SHCtransforming protein ( Shc ), Shc/ GRB2, and Grb2/Son ofsevenless homolog ( SOS ) induce Shc/ GRB2/ SOS/v-Ha-rasHarvey rat sarcoma viral oncogene homolog ( H-Ras )/Mitogen-activated proteinkinase kinase 1 and 2 ( MEK1 and MEK2 )/Mitogen-activated protein kinase3/1 ( ERK1/2 ) cascade, ultimately activating Jun oncogene ( c-Jun ) andc-Myc transcription factors necessary for cell cycle progression [34], [35], [36].

Fyn and JAK2 also activate Phosphatidylinositol-3 kinase ( PIK3)/V-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) )-pathway leading tocell survival [37], [38], [39]. Fynphosphorylates regulatory subunit of PIK3 ( PIK3 reg class 1A ). JAK2 isrequired for the phosphorylation of insulin receptor substrate IRS-1. The role ofIRS-1 is to provide docking sites for PIK3 reg class 1A that activatescatalytic subunit ( PIK3 cat class 1A ) [40]. Adaptor proteinc-Cbl, which is phosphorylated by Fyn, in complex with PIK3 reg class1A and GRB2, resulting in the activation of PI3K [41].

JAK2 also phosphorylates Phospholipase C gamma ( PLC-gamma ), activatingProtein kinase C delta ( PKC-delta ) via Diacylglycerol ( DAG ) [2], [42]. PKC-delta phosphorylates and activates STAT3downstream of Prolactin receptor signaling [43].

The Prolactin receptor dependent interactions of NEK3 with VAV 1 andVAV2 guanine nucleotide exchange factors ( VAV1 and VAV2 ) and Tecwith VAV1 regulate cytoskeleton remodeling via activation of small GTPases (Rashomolog gene family member A ( RhoA ) and Ras-related C3 botulinum toxin substrate1 ( Rac1 )) [10], [11].