Phosphoinositide-specific phospholipase C in health and disease

Phospholipases are widely occurring and can be found in several different organisms, including bacteria, yeast, plants, animals, and viruses. Phospholipase C (PLC) is a class of phospholipases that cleaves phospholipids on the diacylglycerol (DAG) side of the phosphodiester bond producing DAGs and phosphomonoesters. Among PLCs, phosphoinositide-specific PLC (PI-PLC) constitutes an important step in the inositide signaling pathways. The structures of PI-PLC isozymes show conserved domains as well as regulatory specific domains. This is important, as most PI-PLCs share a common mechanism, but each of them has a peculiar role and can have a specific cell distribution that is linked to a specific function. More importantly, the regulation of PLC isozymes is fundamental in health and disease, as there are several PLC-dependent molecular mechanisms that are associated with the activation or inhibition of important physiopathological processes. Moreover, PI-PLC alternative splicing variants can play important roles in complex signaling networks, not only in cancer but also in other diseases. That is why PI-PLC isozymes are now considered as important molecules that are essential for better understanding the molecular mechanisms underlying both physiology and pathogenesis, and are also potential molecular targets useful for the development of innovative therapeutic strategies. Phospholipases are widely occurring and can be found in several different organisms, including bacteria, yeast, plants, animals, and viruses. Phospholipase C (PLC) is a class of phospholipases that cleaves phospholipids on the diacylglycerol (DAG) side of the phosphodiester bond producing DAGs and phosphomonoesters. Among PLCs, phosphoinositide-specific PLC (PI-PLC) constitutes an important step in the inositide signaling pathways. The structures of PI-PLC isozymes show conserved domains as well as regulatory specific domains. This is important, as most PI-PLCs share a common mechanism, but each of them has a peculiar role and can have a specific cell distribution that is linked to a specific function. More importantly, the regulation of PLC isozymes is fundamental in health and disease, as there are several PLC-dependent molecular mechanisms that are associated with the activation or inhibition of important physiopathological processes. Moreover, PI-PLC alternative splicing variants can play important roles in complex signaling networks, not only in cancer but also in other diseases. That is why PI-PLC isozymes are now considered as important molecules that are essential for better understanding the molecular mechanisms underlying both physiology and pathogenesis, and are also potential molecular targets useful for the development of innovative therapeutic strategies. Phospholipases are quite common enzymes that are present in a broad range of organisms, including bacteria, yeast, plants, animals, and viruses. Phospholipase C (PLC) constitutes a class of enzymes that cleave phospholipids on the diacylglycerol (DAG) side of the phosphodiester bond. In plants, a phosphatidylcholine-specific PLC (PC-PLC) has been recently identified: this PLC acts preferentially on phosphatidylcholine, even though it can also act upon other lipids, such as phosphatidylethanolamine, therefore giving rise to a class of nonspecific PLCs (1.Nakamura Y. Awai K. Masuda T. Yoshioka Y. Takamiya K. Ohta H. A novel phosphatidylcholine-hydrolyzing phospholipase C induced by phosphate starvation in Arabidopsis.J. Biol. Chem. 2005; 280: 7469-7476Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 2.Peters C. Li M. Narasimhan R. Roth M. Welti R. Wang X. Nonspecific phospholipase C NPC4 promotes responses to abscisic acid and tolerance to hyperosmotic stress in Arabidopsis.Plant Cell. 2010; 22: 2642-2659Crossref PubMed Scopus (115) Google Scholar). PC-PLC isoforms are responsible for phosphatidylcholine hydrolysis, producing phosphocholine and DAG, and they have been isolated but not yet cloned from mammalian sources. However, accruing evidence points to multiple implications of these enzymes in cell signaling through MAPK and oncogene-activated protein kinase pathways, as well as programmed cell death, activation of immune cells, and stem cell differentiation (3.Abalsamo L. Spadaro F. Bozzuto G. Paris L. Cecchetti S. Lugini L. Iorio E. Molinari A. Ramoni C. Podo F. Inhibition of phosphatidylcholine-specific phospholipase C results in loss of mesenchymal traits in metastatic breast cancer cells.Breast Cancer Res. 2012; 14: R50Crossref PubMed Scopus (51) Google Scholar). On the other hand, phosphoinositide-specific PLC (PI-PLC) enzymes utilize phosphoinositides as a specific substrate and their metabolism is implicated in a large series of signal transduction pathways. This review is devoted to highlighting PI-PLC, which plays an important role in cell physiology and particularly in signal transduction pathways in mammals. Thirteen kinds of mammalian PI-PLCs are classified into six isotypes (β, γ, δ, ε, ζ, η), according to their structure. Here, we shall point at the molecular features, function, regulation, and splicing variants of these enzymes and discuss their role in disease. PI-PLC hydrolyzes phosphatidylinositol-4,5-bisphosphate (PIP2) to produce DAG and inositol-1,4,5-trisphosphate (IP3) (Fig. 1) which, in turn, activate protein kinase C (PKC) and induce the release of calcium ions from intracellular stores, respectively (4.Poli A. Mongiorgi S. Cocco L. Follo M.Y. Protein kinase C involvement in cell cycle modulation.Biochem. Soc. Trans. 2014; 42: 1471-1476Crossref PubMed Scopus (47) Google Scholar, 5.Follo M.Y. Manzoli L. Poli A. McCubrey J.A. Cocco L. PLC and PI3K/Akt/mTOR signalling in disease and cancer.Adv. Biol. Regul. 2015; 57: 10-16Crossref PubMed Scopus (105) Google Scholar). Since the first report of PI-PLC existence (6.Hokin L.E. Hokin M.R. The incorporation of 32P into the nucleotides of ribonucleic acid in pigeon pancreas slices.Biochim. Biophys. Acta. 1953; 11: 591-592Crossref PubMed Scopus (7) Google Scholar), 13 mammal PI-PLC isozymes have been identified and, at a molecular level, they can be divided into six subgroups: PI-PLCβ(1–4), -γ(1 and 2), -δ(1, 3, and 4), -ε, -ζ, and -η(1 and 2). Interestingly, the structure of these PI-PLC isozymes shows highly conserved domains as well as peculiar characteristics (Fig. 2). In fact, the X and Y domains are two highly conserved regions, whereas the C2 domain, the EF-hand motif, and the pleckstrin homology (PH) domain are regulatory domains that are mingled in a specific manner in PI-PLC subtypes (7.Yang Y.R. Follo M.Y. Cocco L. Suh P.G. The physiological roles of primary phospholipase C.Adv. Biol. Regul. 2013; 53: 232-241Crossref PubMed Scopus (73) Google Scholar). Therefore, each PI-PLC isozyme shows a unique combination of X-Y and regulatory domains, so that each PI-PLC isozyme can have a different regulation, function, and tissue distribution (8.Rhee S.G. Regulation of phosphoinositide-specific phospholipase C.Annu. Rev. Biochem. 2001; 70: 281-312Crossref PubMed Scopus (1219) Google Scholar).Fig. 2Molecular structure of PI-PLC isozymes. Each PI-PLC subfamily is characterized by a different pattern and function of PH, EF, X, Y, and C2 domains. In particular, the PH domain of PI-PLCβ enzymes is bound to G proteins, whereas the same PH domain in PI-PLCγ and PI-PLCδ enzymes interacts with PIP3, in order to activate PI3K or favor the membrane binding, respectively. Moreover, the region between the X and Y domains is important for calcium regulation: in PI-PLCζ and PI-PLCη enzymes this region is important for calcium release and sensitivity, while in PI-PLCγ enzymes there are additional specific domains that are important for calcium interaction. As for PI-PLCε enzymes, there are additional RA domains that interact with RAS and modulate both enzyme translocation and inhibition.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The X and Y domains are usually located between the EF-hand motif and the C2 domain, and are composed of α-helices alternated to β-strands, with a structure that is similar to an incomplete triose phosphate isomerase α/β-barrel (9.Essen L.O. Perisic O. Cheung R. Katan M. Williams R.L. Crystal structure of a mammalian phosphoinositide-specific phospholipase C delta.Nature. 1996; 380: 595-602Crossref PubMed Scopus (516) Google Scholar). Conversely, the PH domain, although being a membrane-phospholipid binding region along with the C2 domain, has other specific functions according to the different isozymes. For instance, in PI-PLCδ1, the PH domain binds PIP2 and contributes to the access of PI-PLCδ1 onto the membrane surface (10.Paterson H.F. Savopoulos J.W. Perisic O. Cheung R. Ellis M.V. Williams R.L. Katan M. Phospholipase C delta 1 requires a pleckstrin homology domain for interaction with the plasma membrane.Biochem. J. 1995; 312: 661-666Crossref PubMed Scopus (111) Google Scholar). On the other hand, the PH domain specifically binds the heterotrimeric Gβγ subunit in PI-PLCβ2 and PI-PLCβ3 isozymes (11.Wang T. Dowal L. El-Maghrabi M.R. Rebecchi M. Scarlata S. 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In fact, the to is the of a series of intracellular calcium the which modulate several molecular that are as and they a fundamental for the of these are and by calcium release from in to PI-PLCζ the That is why a between of and the and function of PI-PLCζ in has been The potential therapeutic role of PI-PLCζ therefore be linked to the of that are in and for them an alternative therapeutic on be useful for the activation C. K. Phospholipase C activation and links to Biol. Regul. 2013; 53: PubMed Scopus Google Scholar). As for the other PI-PLC PI-PLCδ enzymes are a peculiar of enzymes several roles in different and PI-PLCδ1 and share a so that they can play roles in In fact, PI-PLCδ1 is for the of in and while specifically in and the of in the of the it has been that the loss of PI-PLCδ1 and in to Y. K. K. functions of phospholipase and phospholipase Biol. Regul. 2013; 53: PubMed Scopus Google Scholar). PI-PLC isozymes play essential roles in cell by calcium and other intracellular signaling pathways that are important for cell and This that these enzymes have the to and This is particularly important, the regulation of PI-PLCs or signaling pathways can be important for understanding both the physiology and the of important to the development of innovative therapeutic or the of molecular processes.