Development - Prolactin receptor signaling

Prolactin signaling

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

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

The cytoplasmic domain of the Prolactin receptor displays no enzymatic activity, but signals through activation of associated cytoplasmic tyrosine kinases, such as Janus kinase 2 (JAK2), V-src sarcoma viral oncogene homolog and FYN oncogene related 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 and phosphorylation. Activated receptor through JAK2 recruits Signal transducers and activators of transcription (STAT), in particular STAT1, STAT3 and STAT5 (STAT5A and STAT5B), and stimulates STATs tyrosine phosphorylation. The phosphorylated STATs dimmerize and translocate to the nucleus, resulting in the initiation of transcription of Interferon-regulatory factor-1 (IRF-1) and milk protein genes (such as Beta-casein and Lactoglobulin) in lymphocytes and mammary gland cells, respectively [12], [13], [14].

In the nucleus STATs interact with coactivators CBP (CREB binding protein), p300, and N-myc interactor (NMI) [15], [16]. STAT5 transcriptional activation can be cooperatively enhanced by the alpha form of Nuclear receptor subfamily 3 group C member 1 (GCR-alpha) and CCAAT/Enhancer binding protein-beta (C/EBPbeta) to induce the transcription of Beta-casein gene [17]. Prolactin stimulation of mammary cells leads 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 (which regulates cell cycle progression) and the antiapoptotic factor BCL2-like 1 (Bcl-XL) [19], [20].

In response to Prolactin receptor stimulation activated STATs translocate 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 to stimulate the transcription of the immediate early gene IRF-1 in lymphocytes [21], [22], [23]. STAT1 activation of IRF-1 promoter is enhanced by the constitutive factor Sp1 transcription factor (SP1), and coactivators E1A binding protein p300 (p300) and CREB binding protein (CBP) [24], [25].

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

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

Suppressors of Cytokine Signaling (SOCS) gene expression is mediated by STAT3 and STAT1. SOCS1 and SOCS3 involve in negative regulation of JAK2 and STAT5-dependent Beta-casein transcription [30], [31].

Prolactin receptor dimerization also induces the Mitogen-activated protein kinases pathway via JAK2 and Fyn kinases activation [7], [32], [33]. The complex formations of Fyn/ SHC transforming protein (Shc), Shc/GRB2, and Grb2/Son of sevenless homolog (SOS) induce Shc/GRB2/SOS/v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras)/Mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2)/Mitogen-activated protein kinase 3/1 (ERK1/2) cascade, ultimately activating Jun oncogene (c-Jun) and c-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 to cell survival [37], [38], [39]. Fyn phosphorylates regulatory subunit of PIK3 (PIK3 reg class 1A). JAK2 is required for the phosphorylation of insulin receptor substrate IRS-1. The role of IRS-1 is to provide docking sites for PIK3 reg class 1A that activates catalytic subunit (PIK3 cat class 1A) [40]. Adaptor protein c-Cbl, which is phosphorylated by Fyn, in complex with PIK3 reg class 1A and GRB2, resulting in the activation of PI3K [41].

JAK2 also phosphorylates Phospholipase C gamma (PLC-gamma), activating Protein kinase C delta (PKC-delta) via Diacylglycerol (DAG) [2], [42]. PKC-delta phosphorylates and activates STAT3 downstream of Prolactin receptor signaling [43].

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

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