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 . 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 . 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 ,. The initial step in Prolactin action is the binding to specific membranecytokine receptor, Prolactin receptor . 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 , , . 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) , , , , . 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 , , . In the nucleus STAT s interact with coactivators CBP (CREB bindingprotein), p300, and N-myc interactor (NMI ) , . 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 . 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 , . STAT5 factors also induce the transcription of Cyclin D1 (whichregulates cell cycle progression) and the antiapoptotic factor BCL2-like 1 (Bcl-XL ) , . 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, , . 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 ) , . 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 , .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 . In addition, association of 2',5'-oligoadenylate synthetase ( OAS1 ) with theProlactin receptor inhibits STAT1 signaling to the IRF-1 promoter. 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, . Prolactin receptor dimerization also induces the Mitogen-activated proteinkinases pathway via JAK2 and Fyn kinases activation ,, . 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 , , . Fyn and JAK2 also activate Phosphatidylinositol-3 kinase ( PIK3)/V-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) )-pathway leading tocell survival , , . 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 ) . Adaptor proteinc-Cbl, which is phosphorylated by Fyn, in complex with PIK3 reg class1A and GRB2, resulting in the activation of PI3K . JAK2 also phosphorylates Phospholipase C gamma ( PLC-gamma ), activatingProtein kinase C delta ( PKC-delta ) via Diacylglycerol ( DAG ) , . PKC-delta phosphorylates and activates STAT3downstream of Prolactin receptor signaling . 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 )) , .