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Asian Pacific Journal of Reproduction 2012; 1(3): 247-252 247

Contents lists available at ScienceDirect Asian Pacific Journal of Reproduction

Journal homepage: www.elsevier.com/locate/apjr

Document heading 10.1016/S2305-0500(13)60086-X Role of the phosphoinositide signal pathway in the endometrium

Vincenza Rita Lo Vasco*

Department Sensitive Organs, Policlinic Umberto I, viale del Policlinico 155 - 00161 Rome Faculty of Medicine and Odontoiatry, Sapienza University of Rome, Italy

ARTICLE INFO ABSTRACT

Article history: The regulation of concentration triggers physiological events in all types. Received 18 July 2012 Unregulated elevation’ in calcium concentrations is often cytotoxic. In fact, uncontrolled calcium Received in revised form 20 July 2012 levels alter function, regulation, as well as proliferation, secretion and Accepted 25 August 2012 contraction. Calcium levels are tightly regulated. A great interest was paid to Available online 20 September 2012 pathways for their role in mammalian reproduction. The role of phosphoinositide (PI) signal transduction pathway and related phosphoinositide-specific C (PI-PLC) Keywords: in the regulation of calcium levels was actively studied and characterized. However, the role of Abortion PI signaling and PI-PLC enzymes in the endometrium is far to be completely highlighted. In the Women's right present review the role of PI, the expression of selected PI-PLC enzymes and the with United States further signaling systems in the endometrium will be discussed.

1. Introduction rate, the fertilization rate and the embryo developmental rate[7]. The regulation of calcium concentration triggers Less in known about the role of PI signaling and ‘PI- physiological events in all cell types[1]. Unregulated PLC enzymes in the endometrium. Reports from the 80s [2] elevation in calcium concentrations is often cytotoxic’ . In indicated that the PI signal transduction pathway plays a fact, uncontrolled calcium levels alter proteins function, role also in the endocrine regulation of endometrium. In our apoptosis regulation, as well as proliferation, secretion and recent report, we suggested that PI-PLC enzymes might be contraction. Calcium levels are tightly regulated by signal involved in endometriosis. In the present review the role transduction pathways, including the phosphoinositide (PI) of PI, the expression of selected PI-PLC enzymes and the system [1,3]. crosstalk with further signaling systems in the endometrium A great interest was paid to PIs for their role in mammalian will be discussed. reproduction. In myometrium, the role of PI signal 2. PI signal transduction pathway transduction pathway and related Phosphoinositide-specific (PI-PLC) enzymes in the regulation of calcium levels was actively studied and characterized. PIs are minority acidic present in the Downstream products of PI-PLC activity are known to membranes of eukaryotic cells[8]. The principal role of PIs play a role in the contraction of uterine smooth muscle is instructional. ’Each compartment uses a cells following the activation of muscarinic and oxytocin characteristic PI s pattern, which attracts a specific panel receptors in the guinea pig myometrium[4,5]. PI-PLC 毱 of proteins. PIs regulate the activities of integral membrane is exclusively present in the spermatic cells. proteins. Many ion channels of the plasma membrane PI-PLC 毮4 is required for the zona pellucida-induced are regulated by the levels of acrosome reaction[6]. In mice, the mutation of the gene 4,5-bisphosphate (PIP2), which is the principal substrate of which codifies for Pi-plc 毬1 reduces the acrosome reaction -stimulated PI-PLC[9]. Over 150 different molecules can activate PI-PLC. Once activated, the PI-PLC cleaves

*Corresponding author: Department Sensitive Organs, Policlinic Umberto I, viale the polar head group of PIP2, a structural component of the del Policlinico 155-00161 Rome, Faculty of Medicine and Odontoiatry, Sapienza plasma membrane[9-11], generating trisphosphate University of Rome. (IP3) (DAG) E-mail: [email protected] and diacylglycerol , both crucial molecules in Vincenza Rita Lo Vasco/Asian Pacific Journal of Reproduction (2012)247-252 248 signal transduction[12]. IP3, a small water-soluble molecule, of the Gq subfamily. G proteins mediate the intracellular diffuses rapidly to the , where it releases calcium signalling by coupling to GPCRs[22,23]. The - from the . DAG remains bound to activated -activated kinase (MAPK) pathway the membrane, exerting two potential signalling roles[13]. can be activated by G毬毭 acting at the Shc protein, by G毩 First, it can be further cleaved to release arachidonic acid, q-stimulated PKC acting at Raf, and by a PKC-independent which either acts as a messenger or is used in the synthesis pathway[24]. GTPase activity in the GGTPase activity in the of eicosanoids. Therefore, DAG is probably involved in the subunit promotes re-association of GDP-bound GGTPase cascade. Moreover, recent evidences suggested activity in the subunit with G毬毭. The specificity of that PI-PLC might be involved in the inflammation response to a given in each cell type depends on the cascade[14]. Second, DAG activates C (PKC). expression and coupling of specific receptors, G proteins, The calcium levels enhancement induced by IP3 moves PKC and effectors. In addition to direct stimulation by G proteins to translocate from the cytoplasm to the cytoplasmic face of of effectors that initiate signalling pathways, there can be the plasma membrane[15]. The translocation activates PKC, cross-talk among downstream effectors of these pathways[25]. which phosphorylate specific or threonine residues (PKA), activated by G毩s stimulation of on further target proteins[16]. , can inhibit both PI-PLC activation and the [26,27] 3. PI-PLC family MAPK pathway . Also ion channels can be regulated by catalysed by PKA, PKC and other effectors of the signalling pathway. : the Ras In , the PI-PLC family comprises a related group super-family of small GTPases comprises more than 150 of multi-domain proteins[17]. Thirteen mammalian enzymes members[28]. These molecular switches fulfill critical roles were identified, divided into six sub-families on the basis of in physiologic and pathologic events, including regulation of structure and activation mechanisms: 毬(1-4), 毭(1, 2), 毮(1, , differentiation, survival, polarity, shape, 3, 4), 毰(1), 毱(1), and 毲(2)[17]. movement, regulation of , vesicle transport, PI-PLC subfamiliesN share a conserved core architecture and many other activities. An enormous number of upstream containing an -terminal pleckstrin (PH), followed by activators and regulators of Ras GTPases were indentified. ( ) a series of elongation factor handC motifs EF , a complex Upon the other side, many different proteins are downstream catalytic domain (X-Y) and a -terminal PKC conserved effectors of activated GTP-bound forms of Ras GTPases. An ( )[18-20] regionN 2 domain C2 . In the catalytic domain, the extensive crosstalk among pathways involving Ras GTPases C-terminal X region, of 65 aminoacids, binds calcium. The results in a complex signalling network. Many GPCR- -terminal Y region, of 115 aminoacids, binds primarily the initiated events also activate Ras GTPases further increasing substrate. crosstalk. eg. Beside this common core, further domains, peculiar to each Activation of GPCRs that couple to other G proteins ( , sub-family, contribute to specific regulatory mechanisms. Gi) can also promote the PI signalling. PI-PLC 毬2 and PI- Isoforms within sub-families share sequence similarity, PLC 毬3 seem to be directly activated by G毬毭 dimers specific domains, molecular effectors and targets, confirming released from G proteins. The C terminal domain of PI- the versatility of the interactions at the cellular membrane PLC 毬 subfamily is necessary for membrane association, and its proximity. G毩q-dependent activation, and promotion of the GTPase 4. PI-PLC regulation activity of G毩q and related 毩-subunits. G毬毭 was supposed to interact with both the PH domain and the catalytic core of PI-PLC 毬2 and PI-PLC 毬3. Growth factors The PI-PLC family of enzymes covers a broad spectrum promote PI signalling involving receptor autophosphorylation of interactions that contribute to membrane recruitment, and generation of phosphotyrosine binding sites for PI- including binding to PI, interaction with small GTPases from PLC 毭 enzymes on the activated receptor[29,30]. Also small Ras and Rho families or heterotrimeric GTP-binding protein GTPases of the [31] may activate selected (G protein) subunits, recognition of specific sites in receptor PI-PLC isoforms such as PI-PLC 毬2, PI-PLC 毭2, and PI- and non-receptor tyrosine and interaction with lipid PLC 毰 [32]. PI-PLC 毬3 also binds Rac, although with lower components of the cell membranes. Two major mechanisms affinity. were described in receptor-promoted regulation of PI-PLC 5. Estrogens and PI-PLC enzymes[18-20]. G proteins: activating molecules, such as and stimulate G-protein-coupled receptors In rat uterus, estrogen receptors probably mediate (GPCRs) to activate ubiquitously expressed members of G rapid signaling events[33,34], resulting in modification of protein family. The G protein subunits are classified into [35,36]. Thus, also in this case, the effect of subfamilies that couple to different effectors[21]. Three 17毬-estradiol depends on the receptors expressed in subunits (毩,毬,毭) comprise the G proteins. In the inactive each tissue. In immature mice, the estrogen receptors state, the G毩 subunit binds GDP. Receptor activation by erythrocyte sedimentation rate 1 (ESR1) and ESR2, present ligand stimulates GDP-GTP exchange on the G毩 subunit, in uterine stroma and , differently respond to 17 and the activated GTP-bound G毩 subunit dissociates from 毬-estradiol, which increases the expression of ESR1 and the G毬毭 complex. Both the G毩 and G毬毭 subunits can decreases the expression of ESR2. 17毬-estradiol controls influence the activity of effector molecules. In instance, PI- the uterine activities, involving genomic responses, activated PLC 毬 isozymes are directly activated by G毩-subunits by the binding of the estrogen receptors on estrogen- Vincenza Rita Lo Vasco/Asian Pacific Journal of Reproduction (2012)247-252 249 responsive elements (EREs) present in the region of 毬1, 毬3, 毮1 and 毮3 isoforms. However, the expression 17毬-estradiol-regulated genes[37]. This event is biphasic. differed in endometriosis tissues with respect to normal Within the first hours, hyperemia and uterine imbibition endometrium. In women affected with endometriosis, PI- was observed. After 24-72 h, epithelial cells proliferation PLC 毬1, PI-PLC 毬3 and PI-PLC 毮3 were expressed in the and differentiation occurs. Furthermore, 17毬-estradiol- eutopic endometrium. PI-PLC 毬1, and PI-PLC 毬3 were mediated regulation of IGF1 transcription and uterine growth expressed in ectopic tissues. PI-PLC 毮1 was expressed involves the direct binding of ESR1 to EREs. 17毬-estradiol exclusively in the uterosacral ligament localization of the responses in the uterus may also occur independently ectopic tissue, indicating that the expression of PI-PLC of ERE-mediated transcription, probably involving non enzymes differs in the normal endometrium of unaffected classical ESR1 signaling mechanisms, such as protein- woman compared to endometriosis affected patients. The to-protein interactions with transcription factors. A non- expression levels of PI-PLC 毬1 were higher in the normal genomic signaling from membrane ESR1 contributing to 17 endometrium. The concentration of PI-PLC 毬1 was 毬-estradiol-mediated modulation of gene transcription moderately lower in the eutopic endometrium and much was also described. In mice uteri, GPER1 mediates lower in the ectopic tissue. Remarkably, different expression the rapid signaling cascade. The activation of GPER in of PI-PLC 毬1 was also described during astrocyte epithelial cells enhances negative regulatory actions in activation after lipopolysaccharide (LPS) stimulation[41,42], the stroma, inhibiting ERK/12 and ESR1 phosphorylation suggesting its involvement in the cascade of events following signals, which are essential for the onset of 17毬-estradiol- inflammatory . In endometriosis, the PI-PLC 毬1 regulated uterine epithelial cell proliferation[37]. ESR1, transcript decreases in the ectopic endometrium, probably ESR2 and GPER mediate rapid signaling events activating related to dysregulation of the activity that PI-PLC 毬 different downstream pathways, including the MAPK, 1 plays in the cell control. However, the role of PI- phosphatidylinositol 3-kinase and PI-PLC pathways, which PLC 毬1 remains to be elucidated. The levels of PI-PLC 毬 in turn modulate transcription. 17毬-estradiol promotes 3 resulted higher in the endometriotic tissue localized in the rapid effects on the rat endometrium through activation uterosacral ligament compared to the normal, to the eutopic of PI-PLC mediated PI hydrolysis and requires nucleo- endometrium and to the ectopic localization in the ovarian cytoplasmic shuttle of ESR1. GPER probably plays an cyst. PI-PLC 毬3 findings were controversial compared to additive role to this event. Membrane initiated our previous studies. In fact, down-regulation was described signaling was suggested to be involved in benign and during astrocyte activation after LPS stimulation[8]. PI-PLC malignant cells of several tissues. These effects occur from 毮1 was down-regulated exclusively in endometriosis. PI- seconds to minutes after administration of 17毬-estradiol PLC 毮3, expressed in the normal and eutopic endometrium, and involve the rapid activation of many signaling molecules was not expressed in the ectopic tissues independently (16, 19, 41), including PI-PLC enzymes. Treatment with 17 from the establishment site. That is an interesting point in 毬-estradiol induced a rapid increase on total (3H)-inositol that one endometriosis susceptibility locus was localized phosphate accumulation in the endometrium mediated on chromosome 17 (17q21)[43], a localization consistent by PI-PLC activation. Pharmacological inhibition of PI- with the region where PLCD3 (OMIM *608795), the gene PLC with the specific inhibitor U73122 decreased the total which codifies for PI-PLC 毮3, maps. The endometriosis (3H)-inositol phosphate accumulation. Pre-treatment with susceptibility locus on 17q21 might be related to PLCD3 the estrogen receptors antagonist ICI 182, 780 blocked mapping and PI-PLC 毮3 might be involved in the disease. ( ) the total 3H -inositol phosphate accumulation induced 7. Molecular function and regulation of PI-PLC by 17毬-estradiol. These data indicate that ESR1 acts as enzymes expressed in the human endometrium an upstream regulator for total( 3H)-inositol phosphate accumulation. GPER also seems to contribute to PI-PLC pathway activation in uterus, and mRNA for GPERIn vivowas Literature data lack about the specific role and regulation detected in the endometrium from rat in estrus. of PI-PLC 毬 and 毭 in the human endometrium, although administration of G-1, a selective agonist of GPER, failed some isoforms belonging to these sub-families resulted to activate expression of Wnt-4, -2, IGF-1 or expressed. However, the regulation mechanism of some E1 in uterus[38]. GPER may play a role in uterine isoforms were analysed in other tissues. Enzymes in physiology, since G-1 and ICI 182, 780[39,40] induced a rapid the PI-PLC 毬 sub-family share the structural features time-dependent increase in total (3H)-inositol phosphate present in other sub-families, and are characterized by accumulation in the endometrium. The G-1-mediated elongated C-terminus about 450 aminoacidic residues long, effects were blocked by pretreatment of the endometrium containing interacting sites for Gq and for other functions with G15 and PI-PLC inhibitors, suggesting that the axis such as membrane binding and nuclear localization[17,28]. GPER1-PLC is also involved in this intracellular pathway. In mammals, splicing variants for each PI-PLC 毬 isoform 6. PI-PLC isoforms in the human endometrium were identified. These enzymes are regulated by G proteins with high GTPase stimulating (GAP) activity. Mammalian PI- PLC 毬 enzymes are differentially distributed in tissues. PI- Many studies were performed to investigate each PI- PLC 毬1 is the most widely expressed, especially in specific PLC isoform and the interacting molecules, but their regions of the brain. PI-PLC 毬1 exists as alternative potentialities are far to be highlighted. In our previous splicing variants PI-PLC 毬1a and -毬1b, which differ studies, we identified a peculiar panel of expressed PI-PLC in C-terminal residues[39]. In the cytoplasm, PI-PLC 毬 isoforms in normal human endometrium, namely PI-PLC isoforms function as effectors for receptors belonging to the Vincenza Rita Lo Vasco/Asian Pacific Journal of Reproduction (2012)247-252 250 superfamily. They are activated by a variety of placental development[16], including reduction of vessels stimuli and require special combinations of G毩 and G毬毭 number in the labyrinth architecture. Interestingly, Plcd1/d3 subunits to couple to the effector. Phosphatidic acid (PA) can double null mice embryos supplied with a normal placenta activate PI-PLC 毬 enzymes, suggesting a role for PA in the by the tetraploid aggregation method[60] survived beyond regulation of GPCR signal transduction mediated through E14.5. Placentas of rescued Plc毮1/-毮3 double null mice PI-PLC 毬1 homodimerization[44]. With the exception of PI- embryos contained many maternal and embryonic vessels, PLC 毬4, PI-PLC 毬 isozymes are also activated by G毬毭 indicating that the embryonic lethality is caused by a defect dimmers[45-47]. The relative sensitivity of PI-PLC 毬 enzymes in trophoblasts. Therefore, PI-PLC 毮1 and PI-PLC 毮3 are to G毬毭 subunits differs from that to Gq毩 subunits. PI- essential in trophoblast/placenta development. Interestingly, PLC 毬1 is the least sensitive to G毬毭[11,45,46]. The G毬 homozygous deletions of the murine chromosome 9 region 毭 dimer interacts with PI-PLC 毬1, 毬3, and with high containing a few genes, including Plcd1, result in phenotype affinity PI-PLC 毬2[48]. G毩q subunit seems to be essential abnormalities, such as alopecia in both genders and male for PI-PLC 毬 activation and cannot be replaced by G毬毭 infertility. . Two different regions of PI-PLC 毬 interact with Gq毩 and PI-PLC 毮1 was also suggested to be an anti-. G毬毭 subunits. Male and female Plcb1 knock-out mice PLCD1, the human gene which codifies for PI-PLC 毮 exhibited impaired’ reproductive behaviour. Interestingly, 1, maps in 3p22 chromosomal region, which is frequently female mice s reduced fertility was probably related to deleted in esophageal squamous cell carcinoma (ESCC) abnormal control of ovulation, whilst the impairment of [61]. Absence of PLCD1 was frequently detected in both male mice infertility is probably due to abnormal behaviour. primary ESCCs and ESCC cell lines. Introduction of PLCD1 Noteworthy, hormones regulate the reproductive processes into ESCC cells suppresses the tumorigenic ability. In through GPCR, which activate a number of enzymes, addition, down-regulation of PI-PLC 毮1 protein seems to including PI-PLC 毬. significantly correlate with ESCC metastasis. The observation PI-PLC 毮 sub-family is considered the most basic of hyperprasia and enhanced proliferation in the skin of due to its simple structure, and probably was the first to Plcd1 null mice suggests that PI-PLC 毮1 might play a appear in primitive eukaryotes. PI-PLC 毮 sub-family is suppressive role in the development and progression of the most sensitive to calcium concentrations[49,50]. Tissue ESCC. Moreover, DLC-1[62], a gene frequently deleted in liver ( ) [62] transglutaminasein vitro 栻 TG栻 associates and activates PI-PLC , shares high homology with the rat p122 Rho GAPin vivo. 毮1 [51]. TGII has both transglutaminase activity and DLC-1 inhibited human cancer and GTPase activity. Expression of TG栻 mutants lacking the tumorigenicity in nude mice. Therefore, p122 might function interaction with 毩-adrenoreceptor (毩AR) or PI-PLC 毮1 as an anti-oncogene by synergic interaction with PI-PLC reduced the increase in intracellular calcium[52], suggesting 毮1 and by modulating the Rho-mediated reorganization the involvement of PI-PLC 毮1 in 毩AR signaling. The Rho of [63]. PI-PLC 毮1 has both nuclear export and GTPase-activating protein (RhoGAP) p122 directly activates import sequences that contribute to its shuttling between the PI-PLC 毮1[53]. Microinjection of the GAP domain of p122 cytoplasm and nucleus[63]. PI-PLC 毮1 is generally found in suppressed the formation of stress fibers and focal adhesions the cytoplasm of quiescent cells, and may also localize in induced by lysophosphatidic acid, suggesting a specific nuclear structures in the G1/S boundary of the cell cycle[64]. GTPase-activating function of p122 for Rho[54]. Therefore, Suppression of PI-PLC 毮1 by siRNA increases the level p122 synergisticallyin vivo, functions as a RhoGAP and an activator of cyclin E, a key regulator of the G1/S boundary, alters of PI-PLC 毮1 inducing cytoskeletal reorganization. S-phase progression, and inhibits cell proliferation[65]. In Plcd1 null mice presented with hair loss associated addition, transient expression of PI-PLC 毮1 suppressed the with abnormal hair follicle structures and epidermal expression of cyclin E at the G1/S boundary. Therefore, PI- hyperplasia in interfollicle epidermis[55], common findings PLC 毮1 probably plays a role in cell cycle progression. in skin inflammation. The expression of pro-inflammatory , such as IL-1毬 and IL-6, significantly increases 8. Conclusion and infiltration of immune cells is observed[56]. Therefore, lack of Plcd1 results in induction of skin inflammation, successfully treated with anti-inflammatory reagents. Further studies are required to elucidate the role of PI- The Plcd1 null mouse was compared to nude mouse[57], in PLC isoforms in endometrium, with special regard to the which Foxn1 gene is spontaneously mutated[58], leading to crosstalk among the expressed enzymes. Moreover, the insufficient hair keratin mHa3 expression and abnormal extensive network of interactions with G proteins and hair shaft structures[59]. Expression of mHa3 was also oestrogens suggests that the PI-PLC enzymes might act as decreased in the skin of Plc毮1 null mice. In addition, crucial players during the activities of normal endometrium. exogenously expressed Foxn1 induced Plcd1 expression. However, research efforts will be necessary to highlight Plcd1 was abundantly expressed in hair follicles of control the involvement of PI-PLC pathway in endometriosis. In mice, whereas faint expression was observed in hair fact, the different expression of PI-PLC enzymes in normal follicles of nude mice. These results confirm that Foxn1 endometrium with respect to endometriotic counterpart acts as an upstream regulator of PI-PLC 毮1. On the and in different localizations of the shed tissue suggests other hand, PI-PLC 毮1 may be involved in the Foxn1/ that the PI signal transduction pathway might be related mHa3 axis regulation. Although Plcd3 null mice showed to endometriosis pathogenesis. Our previous studies about no abnormalities, Plcd1/d3 double null mice resulted the role of PI-PLC in inflammation suggest that the PI in embryonic lethality at E11.5-E13.5 due to defects of transduction system might act a role interfering with the Vincenza Rita Lo Vasco/Asian Pacific Journal of Reproduction (2012)247-252 251 inflammation cascade widely described in the disease. [14]Lo Vasco VR, Fabrizi C, Fumagalli L, Cocco L. Expression of phosphoinositide specific phospholipase C isoenzymes in cultured This interesting hypothesis opens the way to further J astrocytes activated after stimulation with Lipopolysaccharide. studies addressed to analyze the activity and regulation Cell Biochem 109(5 of PI-PLC isoforms in the endometrium, and to delineate 2010; ): 1006-1012. [15]Nishizuka Y. Studies and prospectives of the their relationship with inflammation, representing a Cancer 63 promising approach in order to develop novel molecular family for cellular regulation. 1989; (10): 1892-1903. therapeutic strategies for endometriosis and, probably, for [16]Nakamura Y, Hamada Y, Fujiwara T, Enomoto H, Hiroe T, Tanaka S, et al. Phospholipase C-delta1 and -delta3 are essential other endometrial diseases. Finally, studies addressed to Mol Cell Biol in the trophoblast for placental development. 2005; identify signal transduction pathways interacting upstream 25 and downstream with the PI-PLC system might allow the : 10979-10988. identification of further molecular targets useful to design [17]Suh PG, Park J, Manzoli L, Cocco L, Peak JC, Katan M, et al. Multiple roles of phosphoinositide-specific phospholipase C novel molecular strategies for therapy. BMB Reports 41 isozymes. 2008; : 415-434. [18]Ellis MV, Katan M. Mutations within a highly conserved Conflict of interest statement sequence present in the X region of phosphoinositide-specific Biochem J 307 phospholipase C-delta 1. 1995; : 69-75. We declare that we have no conflict of interest. [19]Williams BL, Irvin BJ, Sutor SL, Chini CC, Yacyshyn E, Bubeck Wardenburg J, et al. 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