Open Journal of Genetics, 2013, 3, 201-215 OJGen
http://dx.doi.org/10.4236/ojgen.2013.33023 Published Online September 2013 (http://www.scirp.org/journal/ojgen/)
An update on the role of prokineticins in human
reproduction-potential therapeutic implications
Kulvinder Kochar Kaur1*, Gautam Allahbadia2, Mandeep Singh3
1Dr Kulvinder Kaur Centre for Human Reproduction, Jalandhar, India
2Rotunda—A Centre for Human Reproduction, Mumbai, India
3Swami Satyanand Hospital, Jalandhar, India
Received 8 July2013; revised 5 August 2013; accepted 13 August 2013
Copyright © 2013 Kulvinder Kochar Kaur et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Objective: Prokineticin-1 (PROK1) is a recently de-
scribed protein with a wide range of functions in-
cluding tissue specific angiogenesis, modulation of
inflammatory responses and regulation of haemato-
poiesis. PROK1 has been found in the steroidogenic
organs like ovary, testis, adrenal and specially pla-
centa and they have been found to have a role in de-
velopment of the olfactory system and GnRH system.
The aim was to update the role of PROK1 and
PROK2 in human reproduction since the review was
provided by Maldono-Perez (2007) on the potentials
of prokineticins in reproduction. Design: A review of
international scientific literature by a search of Pub-
med and the authors files was done for citation of
articles relevant to prokineticins in reproduction, be
it its role in ovary, testis, uterus with special emphasis
on implantation, normal pregnancy, in labour, patho-
physiological states like tubal pregnancy, pcos, vari-
ous genital tumours, and cases of isolated hypogo-
nadotropic hypogonadism with mutations with
PROK2/ PROKR2 and studies detailing functional
mechanisms. Results: In the normal cycle, PROK1 has
been found to have important roles in implantation,
regulating several genes like COX-2, IL-8, IL-11,
CTGF related to imp lantation. Initially m urine studies
revealed a critical role of PROK2 pathway on olfac-
tory bulb morphogenesis and GnRH secretion which
was accidentally discovered and since then several
studies on mutations in PROK2/PROKR2 showed
that they underlie some case of KS in humans. Al-
though in mouse heterozygote state is not associated
with clinical phenotype, most of huma n mu tat ion s ar e
heterozygous. Conclusions: Role of PROK-1 in the
process of implantation, with a deeper understanding
of the process success rates in IVF and ART can be
improved, besides understanding the pathophysiology
of tubal pregnancy. Further presence in ovarian folli-
cles of PROK1 can be used to plan a strategy for
treating pcos. Developme nt of a ntagoni sm of PROK’ S
may be a helpful strategy in treating preterm labour.
Keywords: Prokineticin 1; Prokineticin Receptor 2;
Kallmanns Syndrome; Implantation;
GnRH Development
1. INTRODUCTION
The prokineticins (PROK) are a family of two multifunc-
tional secreted proteins called prokineticin 1 (PROK1) [1]
and PROK2, alias Bombina variegate 8 (Bv 8) [2]. The
names PROK1 and PROK2 were assigned to these pro-
teins by Li et al. to reflect their functions in inducing
specific and potent contractions of the gastrointestinal
tract (GIT). Le Courtier et al. described a growth factor
which induced strong and reproducible mitogenic re-
sponse in endocrine gland-derived endothelial cells [3].
A similar effect induced by this protein and by vascular
endothelial growth factor (VEGF) lead it to be named
endocrine gland VEGF (EG-VEGF) [4]. The two pro-
teins are structurally unrelated despite several similarities
in the function and control mechanisms.
The gene that encodes human PROK1 is located on
chromosome 1 (1p.13.3) and is encoded by three exons.
The mature human PROK1 peptide consists of 86 amino
acids. The most active PROK2 peptide consists of 81
amino acids and is encoded by a four-exon gene on
chromosome 3 (3p21.1). The additional exon of PROK2
gene can be actively spliced resulting in longer isoform
PROK2 L (102 amino acids) whose function is not well
understood [5]. The PROK have been shown to regulate
*Corresponding author.

K. K. Kaur et al. / Open Journal of Genetics 3 (2013) 201-215 202
Angiogenesis [6], neuron genesis [7], pain sensation [8]
intestinal contraction [1], haematopoiesis [4], immune
response [9] and reproduction [10].
PROK bind to two closely related G-protein coupled
receptors (GPCR) known as prokineticin receptor1
(PROKR1) and PROKR2; with both receptors being able
to bind PROK1 and PROK2 with similar affinities [11].
Mature PROK1 and PROK2 are ligands for the highly
homologous (85%) GPCR, (PROKR1 and PROKR 2
formerly known as GPR73a and GPR73b respectively).
In contrast to high homology exhibited by PROK recap-
tors, the ligands PROK1 and PROK2 share only 44%
aminoacid identity. Respecting the conserved N terminal
AVITGA sequence Kaser et al. (2003) proposed the term
AVIT family to classify the prokineticins and their non-
mammalian orthologs [12]. Despite only 45% homology
PROK1 and PROK2 share two conserved feautures dur-
ing molecular evolution essential for bioactivity, 1) a
highly conserved hexapeptide AVITGA sequence and 2)
their N terminal and a distinctive structural motif con-
sisting of ten cysteine residues with five disulphide
crosslinking. The striking differential expression in pro-
kineticins results in PROK1 being predominately expres-
sed in steroidogenic endocrine cells [3], while PROK2 is
mainly expressed in nonsteroidogenic cells of the testis
and the central nervous system.
2. PROKINETICINS IN FEMALE
REPRODUCTIVE FUNCTION
Ovary: Prokineticin 1 (PROK1) is expressed in a dy-
namic way in elements of sex-cord stromal lineage [13],
whereas prokineticin 2 (PROK2) expression is unde-
tectable [14]. During follicle maturation, PROK1 and
vasculal endothelial growth factor (VEGF) expression
are inversely related. In primordial and primary follicles,
there is a high expression of PROK1 in granulosa cells
but no VEGF expression. 1) Maturing secondary follicles
maintain strong PROK1 expression and weak to moder-
ate VEGF expression. 2) In contrast, in the antral folli-
cles PROK1 is expressed at low levels in theca cells,
whereas VEGF expression is very strong in granulosa
cells and moderate in theca cells. 3) In the mature atretic
follicle PROK1 expression is strong again in residual
theca and VEGF expression is weak. The high expres-
sion of PROK1 in atretic follicles might relate to hy-
poxia (via HIF-α) secondary to regressive/apoptotic
changes occurring in these follicles and serves as a signal
for remodeling. 4) In the corpus luteum (CL) the mRNA
expression of PROK1 increases as the CL matures,
whereas VEGF expression is already maximal at the
early luteal phase [14,15]. These differential expression
patterns suggest that VEGF and PROK1 have different
roles in the vascular and nonvascular structures in the CL.
The actions of PROK1 in the ovary are likely to be me-
diated by PROKR1 and PROKR2 which are expressed in
the ovary [11,16]. However their precise localization has
not yet been elucidated. Studies in vitro suggest that
PROK1 has a role in the proliferation and survival of
endothelial cells of bovine corpus luteum [17]. An indi-
rect role for angiogenesis in the CL also has been sug-
gested following the observations that PROK1 can
stimulate the expression of VEGF [18,19].
Practical Implications: Ferrara et al. 2003 studying 13
PCOS human ovaries in comparison to 13 normal ones
found a particular high expression of PROK1 in the Ley-
dig like hilus cells found in the highly vascularized
ovarian hilus. In PCOS ovaries they found strong ex-
pression of PROK1 mRNA in theca interna and stroma,
which are spatially related to new blood vessel. In con-
trast VEGF mRNA expression was most consistently
associated with the granulosa cell layer and sometimes
the theca, but rarely the stroma. These findings of ex-
pression of both VEGF and PROK1 expression in PCOS
ovaries but in different cell types, at different stages of
differentiation, suggested a complementary functions for
the two factors in angiogenesis and possibly cyst forma-
tion [14].
3. POTENTIAL ROLE OF
PROKINETICINS IN PREGNANCY
3.1. Implantation
PROK1 and PROK2 show differential expression across
the menstrual cycle. One of the earliest signs of implan-
tation are hyperaemia and endothelial leakage at the im-
plantation site [20,21]. There is increased endometrial
expression of PROK1 in the midsecretory phase and both
PROK1 and PROKR1 increase in first trimester decidua.
PROK1 and PROKR1 immuno localize to stromal endo-
thelial and glandular epithelial cells of the endometrium
and smooth muscle and endothelial cells in the myo-
metrium [22,23]. Expression of PROK1 has been shown
to be highest during the secretory phase of the menstrual
cycle, and it has been proposed that its role maybe in
vascular differentiation and spiral artery formation dur-
ing the secretory phase. Also, its presence in myometrial
smooth muscle as well as intestinal smooth muscle, sug-
gests that it may also play a role in myometrial contrac-
tions [22].
PROK1 but not PROK2, PROKR1, or PROKR2 ex-
pression peaks during the midluteal window of implanta-
tion. Evans et al. (2008) demonstrated elevated expres-
sion of PROK1 and PROKR1 in first trimester deciduas
in comparison to nonpregnant endometrium. Expression
of both proteins in first trimester deciduas was localized
to glandular epithelium and various compartments within
the stroma and endothelial cells of the microvasculature.
In addition PROK1 but not PROKR1 was detected in

K. K. Kaur et al. / Open Journal of Genetics 3 (2013) 201-215 203
uterine natural killer cells [23]. Gene array analysis of an
endometrial epithelial line stably expressing PROKR1
(PROKR1-Ishikawa) demonstrated, PROK1-PROKR1
signalling regulated genes involved in endometrial re-
ceptivity and implantation of early pregnancy. These
genes included cyclooxy genase 2 (COX2), laeukemia
inhibitory factor (LIF) [23,24], interleukin-8 (IL-8) [25],
and interleukin 11 (IL-11). Studies have demonstrated
regulation of PROK1 by progesterone (P) and human
chorionic gonadotropin (hCG) in the endometrium
[22,24,26]. Dual immunohistochemical analysis co-lo-
calized expression of luteinizing hormone (LH)/hCGre-
ceptor, PROK1, PROKR1 and LIF to the glandular epi-
thelial cells of the first trimester decidual tissue. PROK1
enhances adhesion of trophoblast cells to fibronectin and
laminin matrices, which are mediated predominantly via
LIF induction. Hence maternal-embryonic crosstalk in
which embryonic hCG via endometrial PROK1 may play
a pivotal role in enhancing receptivity and maintaining
early pregnancy [24]. Further Cook et al. (2010) demon-
strated the mechanism by which PROK1 modulated
IL-11 expression via a PROKR1 and a calcineurin/nu-
clear factor of activated T cells (NFAT) signaling path-
way, on a calcium, guanine nucleotide binding protein
(Gq/11) and extracellular signal related kinase (ERK)
dependent manner in human endometrium and first tri-
mester deciduas [27]. Overexpression of regulator of
calcineurin 1isoform 4 (RCAN 1-4)—a negative regulator
of calcineurin signaling leads to a reduction in PROK1
induced IL-11, indicating that RCAN 1 - 4 is acting as a
negative regulator of the signaling pathway mediating
IL-11. IL-11 is known to be essential for successful de-
cidualization and implantation. In human endometrial
stromal cells IL-11 has been shown to advance proges-
terone induced decidualization implying a role for IL-11
in preparing endometrium for implantation [28]. Relaxin
and PGE2 have been shown to increase IL-11 mRNA
and protein secretion in decidualized endometrial stromal
cells [29]. The same gene array analysis also identified
connective tissue growth factor (CTGF) as a target for
PROK1 [23]. CTGF is a heparin binding 38 kDa cysteine
rich peptide that belongs to the CCN (Cyr 61, CTGF,
Nov) family of secretory proteins, with biological activi-
ties related to cellular proliferation, differentiation, adhe-
sion, chemotaxis, migration, apoptosis and extracellular
matrix production. It also has a role in regulating im-
plantation and placentation [30,31] with expression being
increased from placentae from women with preeclamsia
compared with normal pregnancy [32]. CTGF expression
was upregulated by PROK1 in early pregnancy decidua
via activetion of the Gq, PLC, cSrc, EGFR, MAPK/ERK
kinase pathway. Treatment of trophoblast derived
HTR-8/Svneo cells with 1 µg/ml CTGF significantly in-
creased adhesion to collagen IV, and differentiation of
the cells into tube like structures in matrigel suggesting
CTGF may contribute to the regulation of trophoblast
conversion of maternal spiral arteries [33]. Mcdonald et
al. 2011 showed that PROK1 signalling via PROKR1
regulated Dickkopf 1 (DKK1) expression, a negative
regulator of canonical Wnt signaling, and its function in
the nonpregnant endometrium and first trimester decid-
uas [34]. DKK1 mRNA expression is elevated during
midsecretory phase of the menstrual cycle and expres-
sion increases further in first trimester deciduas. DKK1
protein expression is localized to glandular epithelium
and stromal cells during the proliferative, early and sec-
retory phases. However expression is confined to the
stroma in the late secretory phase and first trimester de-
ciduas. PROK1 has been shown to regulate the expres-
sion of IL-8 and IL-11 via a Gq-calcium-calcineu-
rin-NFAT signaling pathway. PROK1 induced DKK1
expression in endometrial epithelial cells and decidual-
izes stromal cells stably expressing PROKR1by same
pathway. In this pathway calcium dependent activation
of calcineurin causes dephosphorylation of NFAT, al-
lowing it to translocate to the nucleus and activate NFAT
regulated gene transcription. The calcineurin-NFAT sig-
naling pathway is regulated by RCAN1-4, an endoge-
nous inhibitor which acts to bind to calcineurin and pre-
vent its activation of NFAT (Figure 1). The study by
Mcdonald et al. (2011) confirmed that RCAN1-4 is a
negative regulator of PROK1 mediated DKK1 expres-
sion in epithelial cells proliferation, and in the decidua it
regulate decidualization of the stroma. The calcineu-
rin-NFAT pathway has previously been shown to be in-
volved in regulating endometrial epithelial cell prolif-
eration [35] and endometrial expression of IL-11. DKK1
expression is known to be increased upon decidualization
of human endometrial stromal cells (HESC) in culture
[36,37], and was demonstrated to be elevated in first tri-
mester decidual tissue where it localizes primarily to the
stromal compartment. Recently PROK levels have been
shown to increase in stromal cells decidualized in vitro
[38,39], and PROK1 is increased in decidualized tissue
[23]. When expression of either DKK 1 or PROK1 is
knocked down on primary ESC, there is a decrease in
expression of the markers of decidualization i.e.
-IGFBP1, prolactin, and IL-11 in response to a decidual-
izing stimulus. Both DKK1 and PROK1 lie downstream
of the progesterone (P)/cyclic AMP signaling cascade
with potential for DKK1 to be regulated by P directly
and indirectly via P mediated regulation of PROK1. It
has been proposed that via a negative regulation of cel-
lular proliferation and decidualization, PROK1 mediated
DKK 1 expression contributes to the generation of a re-
ceptive endometrium and dysregulation of PROK1 me-
diated expression of DKK1 may be a contributing factor
to infertility and recurrent pregnancy loss. Su et al. dem-

K. K. Kaur et al. / Open Journal of Genetics 3 (2013) 201-215 204
Figure 1. Schematic Representation of prokineticin 1 (PROK1)
induction of regulator of calcineurin 1 isoform 4 (RCAN1-4))
and interleukin 11 (IL-11). Activation of PROKR1 by PROK1
results in the induction of IL-11 expression. This occurs via
coupling to Gq/11 protein. This results in an intracellular in-
crease in calcium which activates calcineurin and subsequently
dephosphorylates cytoplasmic NFAT. This allows NFAT to
migrate to the nucleus and bind to NFAT binding motifs in the
promoter of IL-11 and induce its transcription. PROK 1 also
upregulates RCAN1-4 expression which acts as a negative
regulator and reduces the level of IL-11 transcription by bind-
ing to calcineurin and hence inhibiting NFAT dephosphoryla-
tion. Gq = Gq protein alpha subunit, Ca2+ = intracellular ion-
ized calcium ERK = extracellular signal regulated kinase,
Cam-calmodulin, can = Calcineurin catalytic subunit, CnB =
Calcineurin regulatory subunit and NFAT = nuclear factor of
activated T cells. Courtesy ref no-16 with permission.
onstrated a correlation between recurrent miscarriages
and genetic polymorphisms in PROK1 and its receptors
[40]. Aberrant elevation of PROK1 expression has also
been associated with impaired decidualization and re-
current miscarriages [38]. EG-VEGF/PROK1 has been
identified as one of the five new biomarkers of human
endometrial receptivity in the natural cycle besides
laminin-β3, microfil associated protein 5, angiopoietin
like 1, and nuclear localized factor 2 [41].
3.2. Proks and the Feto Placental Unit
During the first trimester of pregnancy PROK1 and
PROKR1 are predominantly expressed in syncytiotro-
phoblasts with the highest expression found during cru-
cial hypoxic period of placentation i.e. from 8 - 10 wks
gestation in contrast to VEGF which is mostly localized
to the cytotrophoblast and extravillous trophoblast cells.
PROK1 is also expressed in specialized macrophages
called hofbauer cells in the placental villi from 6 wks of
gestation. PROKR1 mRNA expression was 80 times
more as compared to PROKR2 mRNA in trophoblast [42]
Both PROK and PROKR1 mRNA appear to be regulated
by hypoxia, as supported by the presence of a hypoxic
inducible factor (HIF-α) binding sites in the promoter of
both PROK1 and PROKR1 [3]. Supported bystudies in
the mouse it has therefore been suggested that PROK1
may have a role in trophoblast differentiation and pla-
cental angiogenesis during early pregnancy, negatively
regulate trophoblast invasion and that its circulating lev-
els were significantly higher in preeclampsia patients
[43,44]
3.3. Prok in Third Trimester—Human
Placenta-Inflammatory Mediator
PROK is thought to have a role in immune regulation
affecting differentiation of human bonemarrow cells onto
distinct monocyte derived cell population primed for
release of proinflammatory cytokines. Furthermore on
stimulation with LPS, PROK1 primed monocyte. Macro-
phages expressed higher levels of TNF-α and IL-12 with
a simultaneous decrease of anti-inflammatory IL-10,
demonstrating that PROK, not only stimulates differen-
tiation of monocytes, but also alters their functions by
enhancing their proinflammatory potential [45]. Also in
mouse tumour model and in isolated human immune
cells it has been demonstrated that PROK2 and PROKR2
are upregulated in peripheral monocytes and neutrophils
in response to G-CSF and GM-CSF [46,47]. Encouraged
by their findings e.g. upregulation of IL-8 and COX-2 in
a PROKR1 overexpressing human endometrial epithelial
cell lines, Denison et al. postulated that PROK1 maybe a
novel mediator of inflammatory response in term pla-
centa and found PROK1 and PROKR1 expressed in term
placenta, immunolocalizing to syncytiotrophoblast, cyto-
trophoblast, foetal endothelium and macrophages [48].
PROK1 induced a time dependent increase in expression
of IL-8 and COX-2 which was dependent on Gq, phos-
phorylation of cSrc, epidermal growth factor receptor
(EGFR) and MAPK kinase. PROK1 colocalized with
IL-8 and COX-2 in placenta as revealed by double im-
munoflorescent immunohistochemistry. COX-2 derived
prostaglandins alongside with chemokines such as IL-8
act to activate immune cells, enable vascular permeabil-
ity and inflammatory cell infiltration during labour. Be-
sides this prostaglandins are involved in cervical ripening
and uterine contractions and thereby elevated COX-2 is
an important marker of ongoing labour. Based on this
and microarray analysis revealing expression of PROK2
increasing with the onset of labour in both the myo-
metrium and cervix [49], it was proposed by Gorwiec et
al. (2011) that PROK1 and PROKR1 may constitute an
initiatory pathway for an inflammatory response in third
trimester placenta [50]. PROK’S have also been shown
to directly induce contractility of smooth muscles. Ana-
lysing the promoter regions of PROKS and PROKR’S
highlights their potential regulation by pathways acti-
vated by infectious agents. Hence Catalano et al. (2010)
further proposed that infection could result in premature

K. K. Kaur et al. / Open Journal of Genetics 3 (2013) 201-215 205
activation of PROK expression and signaling in the
uteroplacental unit and this would initiate a premature
inflammatory and contractile cascade leading to preterm
birth (Figures 2 and 3) [51]. Development of antagonism
of PROK action might provide a suitable therapy for pre-
term labour in future that would target both inflammation
and contractile pathways. Brouillet et al. (2010) showed
PROK1 via PROKR1 mediated angiogenic affects,
whereas PROK2 mediated cellular permeability [52].
They further showed hCG regulates PROK’S. It in-
creases PROK1 from placental explants conditioned me-
dium via transcriptional and post transcriptional effects.
These hCG effects were mediated by cAMP via cAMP
response elements present in the PROK1 promoter re-
gion suggesting hCG regulates PROK’s and their recep-
tors [53]. Chronic glucocorticoid (GC) exposure potenti-
ates placental chorionic plate artery constriction, leading
to aberrant fetoplacental vascular resistance in fetal
growth restriction with PROK1 being one of vasoactive
factors altered by chronic GC [54]. Blocking endogenous
EG-VEGF might represent a valuable approach of im-
pairing or inhibiting angiogenesis in steroidogenic de-
rived embryonic tissues and could work as anti cancer
strategy [55].
3.4. Role of Prok in Fallopian Tube and
Ectopic Pregnancy
As highlighted by Jabbour et al. implantation is an in-
flammatory event and it is the proinflammatory signals
which are required for establishment of a receptive en-
dometrium [56]. Smoking and tubal damage from infec-
tion causes a proinflammatory phenotype in the fallopian
tube which is believed to cause upregulation of proin-
flammatory cytokines which induce factors promoting
endometrial receptivity, adhesion and invasion leading to
ectopic pregnancy. PROK’s are one of the family of pro-
teins which cause upregulation of proinflammatory cyto-
kines in the fallopian tube besides activin A, and inter-
leukin 1 (IL-1). Shaw et al. (2010) found that the
PROKR1 expression was increased in fallopian tubes
(FT) from women who were smokers as compared to
nonsmokers. They treated FT explants and immortalized
oviductal epithelial cells (OE-E6/E7) with cotinine (an
active metabolite of nicotine)at levels found in serum of
smokers and found that in vitro PROKR1 expression
were increased in tissue explants and OE-E6/E7 cells
treated with cotinine in vitro which confirmed their in
vivo findings [57]. Also they identified increased expres-
sion of nicotinic acetyl choline receptor alpha-7
(nAChR-α7) in the FT, and demonstrated cotinine sig-
nals through this receptor resulting in increased tubal
PROKR1 expression [57]. In contrast they identified
increased PROKR2 mRNA expression in FT’s of women
with serological evidence of past C. trachomatis infec-
tion. In vitro treatment of same explants with C. tra-
chomatis also resulted in increased PROKR2 expression
very rapidly, confirming their in vivo findings. UV killed
C. trachomatis also resulted in increased PROKR2 sug-
gesting involvement of cell surface Pattern recognition
Figure 2. LPS signaling cascade and putative response ele-
ments in the promoters of the human prokineticins and their
receptors. (A) LPS is the most potent antigenic component of
the gram negative bacterial cell wall and is known to modulate
the expression of various proinflammatory cytokines. LPS
binds to the TLR 4 complex on the cell surface. TLR4 is
thought to function as dimers and requires the co-receptor
myeloid differentiation protein 2 (MD2) for full receptor sensi-
tivity. CD14 and LPS binding protein (LBP) are known to fa-
cilitate the presentation of LPS. LPS-TLR4 binding leads to
activation of transcription factors and complexes such as acti-
vator protein 1 (AP1), Interferon regulatory factor 3 (IRF3) and
nuclear factor of kappa light polypeptide gene enhancer in B
cells (NF-ΚappaB). Translocation of these factors to the nu-
cleusleads to induction of genes that orchestrate the inflamma-
tory response, such as interleukins IL-6, IL-8, prostaglandin
endoperoxide synthase (PTGS2). (B) In silico analysis of the
promoters of the human prokineticins and their receptors
(PROK1, PROK2, PROKR1, and PROKR2) identified re-
sponse elements in all gene promoters which could potentially
respond to LPS stimulation. The promoter sequence for
PROK1 possessed transcription factor binding elements with
the highest matrix scores (reduced likelihood to represent a
false positive transcription binding element) and was Also con-
sereved in the mouse prok1 promoter. Response elements rela-
tive to start codon (+1) for all promoters except PROKR1
where relative to end of first exon, start codon in second exon (/)
TSS-transcriptional start site. Courtesy ref no-51-with permis-
ion. s

K. K. Kaur et al. / Open Journal of Genetics 3 (2013) 201-215 206
Figure 3. Proposed mechanism of action for PROK’s and their receptors in preterm labour in
response to bacterial infection. (A) Bacteria can be introduced to the pregnant reproductive
tract and reach the amniotic cavity and fetus through different routes. As depicted, the most
common route is via the cervix from the vagina which can result in inflammation of fetal
membranes. Subsequent transmission across the membranes can result in infection of amni-
otic fluid and potentially the fetus. (B) TLR4 is expressed in various components of the utero-
placental unit, the cell depicted is stylized to represent any uterine cell. The bacterial compo-
nent LPS can activate TLR4 resulting in the production of inflammatory mediators (COX-2,
IL-8 and IL-6) key to the induction of myometrial contractility, preterm parturition and fetal
injury 1) In addition, activation of TLR4, by LPS results in elevated expression of proki-
neticins and their receptors 2) which results in amplification of inflammatory mediators 3)
inducing fetal inflammatory injury, myometrial contractility, and preterm laboir. The use of
prokineticin receptor antagonists, 4) would inhibit PROK signaling and amplification of the
proinflammatory mediators preventing myometrial contractility, preterm labour and fetal in-
flammatory injury. Courtesy ref no. 51-with permission.
4. PROK’S IN MALE REPRODUCTIVE
FUNCTION
receptor. Since activation of toll like receptor 2 (TLR2)
in the FT epithelium by C. trachomatis had been demon-
strated to lead to the dysregulation of factors involved in
implantation and smooth muscle contractility, (like
PROKR) and they identified activation of TLR2 in the
tubal epithelium with subsequent activation of NF-ΚB in
response to C. trachomatis expression which suggests
TLR2 activation and induction of inflammatory pheno-
type would be an early feature of ectopic pregnancy.
Elevated PROKR2 expression in women with past C.
trachomatis infection without acute infection suggests
that TLR2 may also be responsible for longacting im-
muneresponses generated by C. trachomatis in FT’s [58].
Since PROK’s upregulate LIF and increased LIF expres-
sion in FT at implantation site compared to adjacent sites
has been demonstrated in chronically inflammed tubes
[59], they proposed that PROKR expression in response
to C. trachomatis expression and cigarette smoke may
lead to an increased PROK signaling resulting in upregu-
lation of factors like LIF which signal to embryo regard-
ing the suitably of environment for implantation [58].
PROK1 is expressed from 14 weeks of pregnancy until
term in human fetal testis. In adult testis PROK1 is
strongly expressed in leydig cells (testosterone (Tn) pro-
ducing) only in contrast to VEGF which is expressed in
both leydig and sertoli cells. PROK2 is restricted largely
to primary spematocytes [60,61]. Both PROKR’s are
expressed within testis to vascular endothelial cells. In
human testis PROKR1 is expressed at higher levels as
compared to PROKR2, whereas they are expressed
equally in mouse testis [60]. The 14-wk point is crucial
time for human testis development as with PROK1 ex-
pression, the fetal production of another protein, steroi-
dogenic acute regulatory protein (StAR) involved in Tn
production begins. Onset of PROK1 mediated angio-
genesis at this time may be critical for normal endocrine
function. Angiogenesis-dependent PROK1 secretion may
permit efficient transport of newly secreted Tn to other
target tissues and may allow the transport of steroidogenic
substances and regulatory hormones e.g. gonadotropins

K. K. Kaur et al. / Open Journal of Genetics 3 (2013) 201-215 207
from periphery towards testis [62]. Lin et al. 2002 pro-
posed that like PROK1, PROK2 functions as a mitogen,
chemoattractant, survival factor in adrenal cortical capil-
lary epithelial cells (ACE) [63]. Thus PROK’s function
as regulators of proliferation and formation of fenestrae
in human testis vasculature [60]. In a pilot genome wide
association study, atagged single nucleotide polymor-
phism in close proximity to PROK2 gene has been
shown to be associated with oligozoospermia/azoosper-
mia in men [64]. Collectively these observations suggest
a role of PROK1 pathway in regulating testicular func-
tion and spermatogenesis. Besides that Samsung et al.
2004 found PROK1 expressed in leydig cell tumours but
not in seminomas whereas VEGF a powerful angiogenic
factor was strongly expressed in seminoma but very
weakly in leydig cell tumours [62]. PROK2 expression
has been found to be increased by varicocoele induction
in rat testis and it may have a role in varicocoele induced
infertility [65].
PROK’s expression have been reported in prostate
along with their receptors [1,16,66]. But at the protein
level PROK1 expression has been reported only in hy-
perplastic and cancerous tissue, localized in glandular
epithelial cells and progressively increased with the
prostate cancer [65]. The role innormal prostate is un-
certain as yet.
5. ROLE OFPROK2 PATHWAY IN
REPRODUCTION
PROK2 is localized in hypothalamic regions critical for
GnRH action e.g., preoptic area, arcuate nucleus, and me-
dian eminence. It is also expressed in nucleus accumbens,
premammilary nucleus, islands of calleja and amyg-
dala-regions associated with reproductive and feeding
behavior. It is also present in suprachiasmatic nucleus
and PROK2 expressing neurons extend their connections
to the preoptic area where GnRH neurons reside. There
is ample evidence that circadian signals contribute di-
rectly to neuroendocrine control of reproduction [67,68].
5.1. GnRH Deficiency in PROK2 and PROKR
Knockout Mice
The role of PROK pathway was accidentally discovered
in the murine knock out of prok2 and prokr2 while
studying the role in gastrointestinal motility and a dis-
ruption of neurogenesis of their olfactory bulbs accom-
panied by a dramatic reduction in GnRH expressing cells
in the median POA along with absence of GnRH neu-
ronal projections in the median eminence [69] was found.
These findings were a phenocopy of the anatomical ob-
servations seen in Kallmanns syndrome (KS) in humans
although till then nomurine model to study KS was
available as KAL1 gene had never been located in the
mouse genome. Approximately 50% of prok2 knockout
mice show asymmetrical development of olfactory bulb.
The GnRH neurons that do manage to reach hypothala-
mus are insufficient in numbers/function to initiate re-
productive axis competency. This implies that PROK2
may impact on GnRH neuronal integrity through addi-
tional mechanisms besides olfactory bulb neurogenesis
[7,69]. Since PROKR2 is not expressed in GnRH neu-
rons, elucidation of molecular mechanisms by which
PROK2 system regulates GnRH neuronal development
and function remains a big challenge. The arrested
GnRH neurons formed a fibrocellular mass just beyond
cribriform plate immediately prior to their entry into the
forebrain [70]. Although all prokr2 mice showed a dra-
matic decrease in the olfactory bulb (OB) size [70] only
half exhibit an asymmetric olfactory bulb development
[69], suggesting a potential redundancy between the two
ligands PROK1 and PROK2 in the neurogenesis of OB.
prok2 and prokr2 knockout mice with reduced GnRH
neurons have a low GnRH secretion resulting in low go-
nadotropins and impairment of sexual maturation in both
male and female mice. Male prok2 and prokr2 knockouts
show small seminiferous tubules which lack lumens,
absent haploid spermatocytes and spermatids [69]. Under
normal conditions prok2 is heavily expressed in diploid
spermatocytes after meiotic division, suggesting a possi-
ble role of prok2 in final stages of spermatogenesis. Al-
though in female mice incomplete follicular development
occurs in mice and humans ovarian function gets re-
stored with gonadotropin replacement.
5.2. Genetic Causes of Isolated GnRH Deficiency
and PROK2
To date roughly 32% of a large cohort of GnRH deficient
patients (n = 397) at the Massachussets general hospital
have been linked to atleast one gene mutation knwn to
cause human GnRH deficiency. These include a broad
spectrum of phenotypes: 1) mild defect of GnRH secre-
tion affecting only timing of puberty (delayed puberty), 2)
an intermediary defect presenting as spontaneous puberty
with subsequent development of permanent hypo-
gonadism (acquired HH) or a, 3) severe defect with com-
plete/partial absence of puberty (reviewed in [71]). Early
developmental genes such as KAL1, FGF8, FGFR1,
NELF, CHD7, PROK2 and PROKR2 play a critical role
in embryonic neuronal development and subjects with
mutations in these genes present primarily with KS.
GnRH deficient patients also display a broadspectrum of
nonreproductive phenotypes including facial midline
defects, skeletal abnormalities and renal agenesis that
can provide key clues to the underlying causal gene.

K. K. Kaur et al. / Open Journal of Genetics 3 (2013) 201-215 208
5.3. PROK2 and PROKR2 Mutations in Isolated
GnRH Deficiency in Humans
Following the murine models, Dode et al. (2006) screened
192 unrelated KS patients and found several DNA se-
quence changes in both PROK2 and PROKR2 without
Any functional studies in the missense cases [72]. In
contrast to murine knockout model majority of these rare
sequence variants existed only in heterozygous state with
four patients with heterozygous mutations in PROK2 and
ten patients with heterozygous PROKR2 variants in pa-
tients with overt clinical phenotype. Only four patients
showed a homozygous/compound heterozygous state,
Following that Pittleloud et al. 2007 reported 3 siblings
with GnRH deficiency (two brothers and one sister of
Portuguese ethnicity and all of them harbouredloss of
function homozygous deletion in the ligand, PROK2
which resulted in a biologically inactive 27 amino acid
truncated protein [69]. Subsequently a large number of
predominantly heterozygous loss of function mutations
in both PROK2 and PROKR2 have now been reported in
patients with both KS and nIHH by several groups. (Cole
et al. (2008) [73], Leroy et al. (2008) [74], Sinisi et al.
(2008) [75], Abreu et al. (2008) [76], Canto et al. (2009)
[77], Sarfati et al. (2010) [78], Monnier et al. (2009)) [79].
Balasubriam et al. (2011) found a lot of puzzling observa-
tions after studying combined analysis of murine and hu-
man phenotypes [80].
1) Although neurodevelopmental role of PROK2
pathwayis key in GnRH development there is conspicu-
ous absence of PROKR2 in both developing and mature
GnRH neuron. This is further complicated by the recent
findings of isolated congenital anosmia (ICA) without
gonadotropin deficiency in 25 patients with ICA and
olfactory bulb agenesis in whom detailed phenotype
analysis and coding sequences of KAL1, FGR1, FGF8,
PROK2 and PROKR2 were sequenced. Three PROKR2
mutations previously described in KS, and one new
PROK2 mutation were found and investigation of the
families showed incomplete penetrance of these muta-
tions, which confirms complexity of GnRH neuron de-
velopment in humans [81]. This challenges the proposi-
tion by Balasubramaniam et al. (2011) that an hitherto
unknown early neonatal population expressing PROKR2
may govern the migration of the GnRH neuron by virtue
of their chemoattractive interaction with the developing
OB which shows a high level of PROK2 expression [80].
2) As compared to mice which develop a pure neuro-
developmental phenotype i.e. a combination of olfactory
and reproductive phenotype, humans with PROK2/PRO-
KR2 mutations present with both KS as well as normos-
mic IHH. This observation suggests that PROK2 path-
way plays a key role in both neurodevelopmental and
neuroendocrinefacets of GnRH ontogeny. However stu-
dying the olfactory phenotypic spectrum in IHH patients
Lewkowitz-Shpuntoff et al. 2012 found 31.5% patients
were anosmic, 33.6% hyposmic and 34.9% normosmic
out of 286 cases of IHH studied [82]. Although tradi-
tionally it is believed that KS and nIHH were distinct
clinical entities with KS representing a neurodevelop-
mental phenotype with a primary defect in GnRH neu-
ronal migration, whereas nIHH subjects represent a pure
neuroendocrine defect in GnRH secretion/action. Most
genes identified in subjects with KS have been shown to
play a predominant GnRH migratory role (KAL1, NELF/
PROK2/PROKR2/FGF8/FGFR1) [83], whereas genes
identified in nIHH subjects have been shown to primarily
affect neuroendocrine regulation of GnRH (GnRH1,
GnRHR, TAC3, TACR3, KISS1R) [84]. Thus 1/3 pa-
tients of IHH displaying a hyposmic phenotype of which
39.5% harbored mutations in genes affecting neuronal
migration like KAL1/PROK2/FGF signalling, suggest a
pathophysiological overlap between KS and nIHH, while
all PROKR2 variants were monoallelic and associated
with anosmia/normosmia.
3) While in mice heterozygous gene deletions are re-
portedly normal, in humans mostly clinical syndromes
are found with the heterozygous state. The proposed hy-
pothesis are a) an autosomal dominant mode of inheri-
tance/haploinsufficiency state; b) a dominant negative
effect of mutations; or c) oligogenic interactions with
other genes/nongenic factors. Although an autosomal
dominant state has not been supported [79], oligogenic
interactions with mutations in other genes known to
cause GnRH deficiency have been documented in some
patients with heterozygous mutations in PROK2/PRO-
KR2 [73,77,78]. However a dominant negative role for
the mutations is still possible, requiring allelic dosing
experiments in robust cellular model/organ system to
confirm or refute the hypothesis. 4) Humans having
identical PROK2/PROKR2 mutations show considerable
variations in the expression and penetrance of both their
olfactory and reproductive phenotypes. 5) The in vitro
functional studies of human PROKR2 mutations show
discordant effects on the various intracellular signaling
pathways suggesting unique structure functional rela-
tionship of the PROKR2 missense variants that have
been systematically assessed, some mutations show sig-
nificant impairment of receptor function (L173R, P290S,
W178 S), while others (R85C, R248Q, V331M), prefer-
entially affect either the intracellular calcium influx or
the MAPK signaling cascade (R357W) [73,79]. The in-
tracellular signaling effect of missense variants show
diverse features. The discordant effects of PROKR2 mu-
tations may indicate domain specific effects, with more
detailed characterization will allow mapping of structure
activity relationships and identify critical structural ele-
ments of the PROKR2 receptors. Peng et al. (2011) identi-

K. K. Kaur et al. / Open Journal of Genetics 3 (2013) 201-215 209
fied PROK2 dose dependently increased the cytoplasmic
calcium in cells transfected with WT PROKR2 however
R164 Q mutant (mutation in 2nd intracellular (IL2) loop)
PROKR2 showed normal cell surface expression and
ligand binding capacity, but lost the PROKR2 signalling.
R164 Q mutation disrupted the interaction of IL2 loop to
the Gαq, Gαi, And Gαi6 proteins [85]. A positive-
charged aminoacid at this position is required for proper
function, and the signaling efficacy and potency depends
on the net amount of positive charges. They also showed
that the interactive partner of Arg-164 may localize in
the C terminal five residues of Gαq protein. A series of
mutation analysis indicated that the basic amino acids at
the C terminus of IL2 loop may function cooperatively in
GPCR’s. Studying the variants of first intracellular loop
(ICL 1) of PROKR2 (R80C, R85C and R85H) identified
in patients with HH, Abreu et al. (2012) found that the
R85C and R85H PROKR2 mutations, modestly inter-
fered with receptor function, in contrast to R80C
PROKR2 mutations which lead to marked reduction in
receptor activity. Cotransfection of wild type and R80C
mutant could exert a dominant negative effect on WT
PROKR2 in vitro by interfering with WT receptor ex-
pression, hence identifying importance of Arg 80 in
ICL1 for PROKR2 expression and demonstration that
R80C PROKR2 exerts a dominant effect on WT
PROKR2 [86].
6) Apotential dual effect of PROK2 mutations, as few
male patients with mutations of PROK2 pathway display
spermatogenic abnormalities, despite gonadotrop in
treatment as shown by Sinisi et al. [75] oligozoospermia
persisted suggesting a primary gonadal defect as well. As
outlined in role in testicular function, these observations
suggest a role of PROK2 pathway in regulating primary
testicular function and spermatogenesis. While in con-
trast to men, in women and female mice with PROK2
deficiency ovarian function gets restored with gonad-
otropin replacement.
7) GnRH deficient patients with PROK2/PROKR2
mutations have been shown to be associated with nonre-
productive feautures eg bikinesis and hearing loss has
been seen in a minority of patients of PROK2/PROKR2
mutation, no cleft lip/renal agenesis has been associated
with PROK2 mutations [87]. Also no disturbances in
circadian rhythm/sleep disorders identified although in a
case controlled Japanese study in patients with mood
disorders (151 bipolar patients, 319 with major depres-
sive disorders and 319 controls), Kishi et al. (2009)
found a tagging SNP in PROKR2, associated with major
depressive disorder [88]. Although in prok and prokr
knockout mice increased neonatal mortality is reported it
has only been reported in 1 family by Pitteloud 2007
with PROK2 mutations, but not in other families or
pedigrees with PROK2 mutation [69].
5.4. PROKR2 in Hypothalamic Amenorrhea
Although functional hypothalamic amenorrhea is con-
sidered a reversible form of GnRH deficiency, triggered
by stressors like excessive exercise, nutritional defects,
or psychological distress Caronia et al. (2011) analyz-
ing 55 patients of HA found 6 heterozygous mutations in
7 of 55 patients, of which two were in the PROKR2 gene
(R85H and L173 R), both of which were loss of function
mutations, besides FGR1, GNRHR and KAL1 gene mu-
tations suggesting that there is a genetic predisposition to
HA in view of differing susceptibility in women to de-
velop HA in response to stress [89].
5.5. Role of PROK2 Pathway in Pituitary
Development
With the proposed role of PROK2 Pathway in angio-
genesis and neuronal migration, Reynaud et al. 2012
reported two heterozygous PROKR2 mutations (p. Leu
173 Arg and pArg 85 His) which had been previously
reported in isolated hypogonadotropic hypogonadism
(IHH) and a novel PROKR2 variant (pAla 51 Thr) which
in contrast to other mutations did not impair receptor
signaling. While studying 72 index cases of hypopituita-
rism with pituitary stalk interruption syndrome and thus
proposed a potential role of PROK pathway in pituitary
development and hypothesized that ectopic posterior
pituitary may be a consequence of defective axonal pro-
jections along the pituitary stalk or defective angiogene-
sis of hypophyseal portal circulation [90]. Similarly
McCabe et al. 2013 detected five PROKR2 variants in
patients of congenital hypopotuitarism (CH), including
septooptic dysplasia (SOD). Of 422 patients of complex
forms of CH, they detected 5 PROKR2 variants in 11
patients with SOD/CH, novel p.G371R, and previously
reported p.A51T, p.R85l, p.L173R, and p.R268C-the
latter 3 being known to be functionally deleterious vari-
ants [91]. Downregulation of PROK1 in pituitary ade-
nomas except LH secreting adenomas suggests LH might
be involved in PROK1 secretion [92].
6. OTHER POTENTIAL ACTIONS
In view of various physiological functions, it was pro-
posed by Levit et al. (2011) to identify binding sites of
known antagonists and additional potential binders to
facilitate studying the novel PROKR’s with the view that
blocking PROKR’s may serve as therapeutic tool for
various diseases, including acute pain, inflammation and
cancer. Potential human PROKR ligands with novel
scaffolds identified by ligand based pharmacophore
models derived from known antagonists and virtual

K. K. Kaur et al. / Open Journal of Genetics 3 (2013) 201-215 210
screening performed on Drugbank dataset identified sev-
eral HIV protease inhibitors for which endothelial cell
dysfunction is a documented sideeffect. Their results
suggest that the side effects might be due to inhibition of
the PROKR signaling pathway. Docking of known bind-
ers to a 3D homology model of PROKR1 is in agreement
with the well established canonical TM-bundle binding
site of family A GPCR’S. With the exception of a single
loop residue that might be perused in the future for ob-
taining subtype-specific regulation, their results suggest
an identical TM-bundle binding site for PROKR1 and
PROKR2, and variable regions may provide subtype
specificity [93].
7. CONCLUSIONS—THERAPEUTIC
IMPLICATIONS AND FUTURE
DIRECTIONS
PROK1 has been found to be involved in the process of
embryo implantation and initiation of parturition. It has a
role in the pathogenesis of tubal pregnancy secondary to
smoking, testicular leydig cell tumors, and other cancers.
As PROK1 leads to the expression of various genes
stimulated in endometrium and uNK cells including LIF,
COX-2, IL-8 and IL-11, this helps in understanding the
improved implantation despite knocking off VEGFR2 by
cabergoline [94] in the prevention of OHSS attributable
to role of PROK1 in early angiogenesis. This knowledge
can be used to improve implantation and success rates in
IVF and ART. Inhibiting PROK action may delay the
onset of preterm labour by suppressing myometrial con-
tractility and reducing the premature onset of inflamma-
tory pathways known to be critical for induction of la-
bour. Simultaneously this PROK signaling suppression
may also prove beneficial to preterm neonatal outcome
by reducing inflammation associated injury to the fetal
brain and lungs. Astrategy for prevention of tubal preg-
nancies in smokers can be achieved by understanding
aetiopathogenesis of increased LIF expression in tubal
mucosa and anticancer strategies in male and female
cancers can be evolved.
PROK2 signaling is a critical regulator of olfactory
bulb morphogenesis and sexual maturation in mammals.
Although PROK2 and PROKR2 have emerged as critical
regulators of reproduction with PROK2 and PROKR2
mutations having a role in KS, the exact mode of in-
heritance however remains controversial. The complex
biology of GnRH neuronal development and function has
not been fully understood. The recent discovery of muta-
tions in the PROK2 pathway in human GnRH deficiency
has provided some help, yet many challenges and ques-
tions have been opened up. For e.g., in both murine and
human PROK2/PROKR2 mutations in homozygous state
have provided compelling evidence for the critical role
played by the PROK pathway in embryonic migration of
GnRH neurons. But the presence of PROK2/PROKR2
mutations in nIHH subjects and the reproductive abnor-
malities found in prok knockout mice with partial olfac-
tory bulb development is suggestive a potential role for
PROK2 beyond GnRH neuronal migration. Further
GnRH neurons don’t express PROK receptors which
make the matter further perplexing. Also, although mice
with heterozygous mutations do not show overt defects,
humans with missense mutations present with clinical
phenotypes. Although a monogenic recessive mode of
inheritance has been clearly demonstrated, it has been
done in very few cases. On top of that many of the het-
erozygous mutations have also been identified in clini-
cally unaffected individuals. Moreover a dominant nega-
tive effect of the heterozygous mutations of PROKR2
was not demonstrated by in vitro studies, which argues
against a monogenic dominant transmission. Hence po-
tential digenic and oligogenic transmission has been
suggested. Many of the heterozygous mutations of
PROKR2 have also been identified in clinically unaf-
fected individuals, which raises the question of actual
contribution of PROK’S to the HH phenotype. Potential
digenic and oligogenic transmission [95] is suggestive;
but still further studies are necessary to confirm the ac-
tual pathogenic role of heterozygous PROKR2 mutations
with GnRH neurons not expressing PROK receptors
suggests an intermediary pathway may mediate PROK2
system and the GnRH neuronal network which needs to
be elucidated. The mechanism of PROK signaling is also
ill understood with the interacting proteins, chaperones,
transcription factors or if any 2nd messenger systems
exist need to be unearthed.
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