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 . 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 . 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 , .
The initial step in Prolactin action is the binding to
specific membrane cytokine receptor, Prolactin receptor
. 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 , , .
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)
, , , , .
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 , , .
In the nucleus STATs interact with coactivators
CBP (CREB binding protein),
p300, and N-myc interactor
(NMI) , .
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 . 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 , .
STAT5 factors also induce the transcription of
Cyclin D1 (which regulates cell cycle progression) and the
antiapoptotic factor BCL2-like 1 (Bcl-XL) , .
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 , , . 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) , .
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 , . 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 .
In addition, association of 2',5'-oligoadenylate synthetase
(OAS1) with the Prolactin receptor
inhibits STAT1 signaling to the
IRF-1 promoter .
Suppressors of Cytokine Signaling (SOCS) gene expression
is mediated by STAT3 and STAT1.
SOCS1 and SOCS3 involve in
negative regulation of JAK2 and
transcription , .
Prolactin receptor dimerization also induces the
Mitogen-activated protein kinases pathway via JAK2 and
Fyn kinases activation , , . The complex formations of Fyn/ SHC
transforming protein (Shc),
Grb2/Son of sevenless homolog
Harvey rat sarcoma viral oncogene homolog
(H-Ras)/Mitogen-activated protein kinase kinase 1 and 2
MEK2)/Mitogen-activated protein kinase 3/1
(ERK1/2) cascade, ultimately activating Jun oncogene
c-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 to cell
survival , , .
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) . Adaptor protein c-Cbl,
which is phosphorylated by Fyn, in complex with
PIK3 reg class 1A and GRB2,
resulting in the activation of PI3K .
JAK2 also phosphorylates Phospholipase C gamma
(PLC-gamma), activating Protein kinase C delta
(PKC-delta) via Diacylglycerol
(DAG) , .
PKC-delta phosphorylates and activates
STAT3 downstream of Prolactin
receptor signaling .
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)) , .
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