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Role of the Phosphoinositide Signal Transduction Pathway in the Endometrium

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Role of the Phosphoinositide Signal Transduction Pathway in the Endometrium 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 transduction 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 calcium concentration triggers physiological events in all cell 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 proteins function, apoptosis regulation, as well as proliferation, secretion and Accepted 25 August 2012 contraction. Calcium levels are tightly regulated. A great interest was paid to signal transduction Available online 20 September 2012 pathways for their role in mammalian reproduction. The role of phosphoinositide (PI) signal transduction pathway and related phosphoinositide-specific phospholipase C (PI-PLC) enzymes 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 crosstalk 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 Phospholipase C (PI-PLC) enzymes in the regulation of calcium levels was actively studied and characterized. PIs are minority acidic phospholipids 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 cell membrane 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 enzyme 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 phosphatidylinositol 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 receptor-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 inositol 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 cytoplasm, where it releases calcium signalling by coupling to GPCRs[22,23]. The tyrosine kinase- from the endoplasmic reticulum. DAG remains bound to activated mitogen-activated protein 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 inflammation 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 ligand in each cell type depends on the cascade[14]. Second, DAG activates protein kinase 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 serine or threonine residues Protein kinase A (PKA), activated by G毩s stimulation of on further target proteins[16]. adenylyl cyclase, can inhibit both PI-PLC activation and the [26,27] 3. PI-PLC family MAPK pathway . Also ion channels can be regulated by phosphorylation catalysed by PKA, PKC and other effectors of the G protein signalling pathway. GTPases: the Ras In eukaryotes, 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, cell proliferation, differentiation, survival, polarity, shape, 3, 4), 毰(1), 毱(1), and 毲(2)[17]. movement, regulation of gene expression, 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 Ras superfamily[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 kinases 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 hormones and neurotransmitters stimulate G-protein-coupled receptors In rat uterus, estrogen receptors probably mediate (GPCRs) to activate ubiquitously
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