Phosphoinositide-specific phospholipase C in health and disease
2015; Elsevier BV; Volume: 56; Issue: 10 Linguagem: Inglês
10.1194/jlr.r057984
ISSN1539-7262
AutoresLucio Cocco, Matilde Y. Follo, Lucia Manzoli, Pann‐Ghill Suh,
Tópico(s)Cellular transport and secretion
ResumoPhospholipases 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. The pleckstrin homology domain of phospholipase C-beta(2) links the binding of gbetagamma to activation of the catalytic core.J. Biol. Chem. 2000; 275: 7466-7469Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar), and mediates interactions with phosphatidylinositol-3,4,5-trisphosphate (PIP3) in PI-PLCγ1, where it is required for inducing a phosphoinositide 3-kinase (PI3K)-dependent translocation and activation (12.Falasca M. Logan S.K. Lehto V.P. Baccante G. Lemmon M.A. Schlessinger J. Activation of phospholipase C gamma by PI 3-kinase-induced PH domain-mediated membrane targeting.EMBO J. 1998; 17: 414-422Crossref PubMed Scopus (483) Google Scholar). As for this latter, it is worthwhile to note that PI-PLCγ1 and PI-PLCγ2 isozymes contain an additional PH domain, which is split by two tandem Src homology (SH)2 and SH3 domains, in order to interact directly with the calcium-related transient receptor potential cation channel 3, thereby providing a direct coupling mechanism between PI-PLCγ and agonist-induced calcium entry (13.Wen W. Yan J. Zhang M. Structural characterization of the split pleckstrin homology domain in phospholipase C-gamma1 and its interaction with TRPC3.J. Biol. Chem. 2006; 281: 12060-12068Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). Finally, the C2 and EF-hand motifs are important for the regulation of calcium: the EF-hand motifs, in particular, are helix-turn-helix structural domains that bind calcium ions in order to enhance the PI-PLC enzymatic activity (14.Nakashima S. Banno Y. Watanabe T. Nakamura Y. Mizutani T. Sakai H. Zhao Y. Sugimoto Y. Nozawa Y. Deletion and site-directed mutagenesis of EF-hand domain of phospholipase C-delta 1: effects on its activity.Biochem. Biophys. Res. Commun. 1995; 211: 365-369Crossref PubMed Scopus (38) Google Scholar, 15.Otterhag L. Sommarin M. Pical C. N-terminal EF-hand-like domain is required for phosphoinositide-specific phospholipase C activity in Arabidopsis thaliana.FEBS Lett. 2001; 497: 165-170Crossref PubMed Scopus (61) Google Scholar). As described above, the PI-PLC isozymes have peculiar molecular features, with common conserved domains and specific regulatory domains. Interestingly, among the PI-PLC isoenzymes, PI-PLCβ subtypes distinguish themselves also by the presence of an elongated C terminus, consisting of about 450 residues, which contains many of the determinants for the interaction with Gq alpha subunit as well as for other functions, such as membrane binding and nuclear localization (16.Rhee S.G. Reflections on the days of phospholipase C.Adv. Biol. 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Indeed, the regulation of PI-PLCβ isozymes is peculiar. Most of them may have a high guanosine triphosphatase activating protein (GAP) activity, but not PI-PLCβ1, that can also be regulated by a distinct binding region to phosphatidic acid or is specifically activated by MAPK, therefore playing important roles in cell metabolism (19.Ross E.M. Mateu D. Gomes A.V. Arana C. Tran T. Litosch I. Structural determinants for phosphatidic acid regulation of phospholipase C-beta1.J. Biol. Chem. 2006; 281: 33087-33094Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 20.Cockcroft S. Garner K. Potential role for phosphatidylinositol transfer protein (PITP) family in lipid transfer during phospholipase C signalling.Adv. Biol. Regul. 2013; 53: 280-291Crossref PubMed Scopus (14) Google Scholar, 21.Sánchez-Fernández G. Cabezudo S. García-Hoz C. Benincá C. Aragay A.M. Mayor Jr, F. Ribas C. Galphaq signalling: the new and the old.Cell. Signal. 2014; 26: 833-848Crossref PubMed Scopus (59) Google Scholar, 22.Faenza I. Billi A.M. Follo M.Y. Fiume R. Martelli A.M. Cocco L. Manzoli L. Nuclear phospholipase C signaling through type 1 IGF receptor and its involvement in cell growth and differentiation.Anticancer Res. 2005; 25: 2039-2041PubMed Google Scholar, 23.Martelli A.M. Fiume R. Faenza I. Tabellini G. Evangelista C. Bortul R. Follo M.Y. Fala F. Cocco L. Nuclear phosphoinositide specific phospholipase C (PI-PLC)-beta 1: a central intermediary in nuclear lipid-dependent signal transduction.Histol. Histopathol. 2005; 20: 1251-1260PubMed Google Scholar). Upon PI-PLCβ1 activation in the nucleus, IP3 generation occurs (Fig. 3). IP3 acts as a substrate for inositol polyphosphate multikinase (IPMK), which is located in the nucleus and gives rise to higher inositol phosphates (24.Blind R.D. Disentangling biological signaling networks by dynamic coupling of signaling lipids to modifying enzymes.Adv. Biol. Regul. 2014; 54: 25-38Crossref PubMed Scopus (21) Google Scholar). Moreover, except for PI-PLCβ4, PI-PLCβ isozymes can also be activated by Gβγ dimers (25.Park D. Jhon D.Y. Lee C.W. Ryu S.H. Rhee S.G. Removal of the carboxyl-terminal region of phospholipase C-beta 1 by calpain abolishes activation by G alpha q.J. Biol. Chem. 1993; 268: 3710-3714Abstract Full Text PDF PubMed Google Scholar, 24.Blind R.D. Disentangling biological signaling networks by dynamic coupling of signaling lipids to modifying enzymes.Adv. Biol. Regul. 2014; 54: 25-38Crossref PubMed Scopus (21) Google Scholar, 25.Park D. Jhon D.Y. Lee C.W. Ryu S.H. Rhee S.G. Removal of the carboxyl-terminal region of phospholipase C-beta 1 by calpain abolishes activation by G alpha q.J. Biol. Chem. 1993; 268: 3710-3714Abstract Full Text PDF PubMed Google Scholar, 26.Smrcka A.V. Sternweis P.C. Regulation of purified subtypes of phosphatidylinositol-specific phospholipase C beta by G protein alpha and beta gamma subunits.J. Biol. 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Regulation of purified subtypes of phosphatidylinositol-specific phospholipase C beta by G protein alpha and beta gamma subunits.J. Biol. Chem. 1993; 268: 9667-9674Abstract Full Text PDF PubMed Google Scholar). Although not fully understood, PI-PLCγ1 regulatory mechanisms involve polypeptide growth factor receptors that bind to RTKs, such as the epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor (PDGFR). Besides this, the SH2 domains of PI-PLCγ1 can also mediate the binding to auto-phosphorylated tyrosine residues within the intracellular region of the receptor (29.Kamat A. Carpenter G. Phospholipase C-gamma1: regulation of enzyme function and role in growth factor-dependent signal transduction.Cytokine Growth Factor Rev. 1997; 8: 109-117Crossref PubMed Scopus (83) Google Scholar). Moreover, it is remarkable that PI-PLCγ1 can also be activated downstream of a series of receptors that lack intrinsic tyrosine kinase activity, including the angiotensin II and bradykinin receptors, cytokine receptors, and the T cell receptor (30.Marrero M.B. Paxton W.G. Schieffer B. Ling B.N. Bernstein K.E. Angiotensin II signalling events mediated by tyrosine phosphorylation.Cell. Signal. 1996; 8: 21-26Crossref PubMed Scopus (47) Google Scholar, 31.Venema V.J. Ju H. Sun J. Eaton D.C. Marrero M.B. Venema R.C. Bradykinin stimulates the tyrosine phosphorylation and bradykinin B2 receptor association of phospholipase C gamma 1 in vascular endothelial cells.Biochem. Biophys. Res. Commun. 1998; 246: 70-75Crossref PubMed Scopus (40) Google Scholar, 32.Sozzani P. Hasan L. Seguelas M.H. Caput D. Ferrara P. Pipy B. Cambon C. 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Indeed, several GPCR ligands, such as lipoprotein A, thrombin, and endothelin, can activate PI-PLCε, but PI-PLCε also associates with Rap and translocates to the perinuclear area, where it interacts with activated RTKs (38.Jin T.G. Satoh T. Liao Y. Song C. Gao X. Kariya K. Hu C.D. Kataoka T. Role of the CDC25 homology domain of phospholipase Cepsilon in amplification of Rap1-dependent signaling.J. Biol. Chem. 2001; 276: 30301-30307Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). As for PI-PLCδ1 and PI-PLCη1, they are activated via GPCR-mediated calcium mobilization. In particular, the PI-PLCδ1 isozyme is one of the most sensitive enzymes to calcium, suggesting that its activity is directly regulated by calcium (39.Kim Y.H. Park T.J. Lee Y.H. Baek K.J. Suh P.G. Ryu S.H. Kim K.T. Phospholipase C-delta1 is activated by capacitative calcium entry that follows phospholipase C-beta activation upon bradykinin stimulation.J. Biol. 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On the contrary, secondary PI-PLCs, such as PI-PLCε, are activated by Rho and Ras GTPases, while the activation of other secondary PI-PLCs (mainly PI-PLCδ1 and PI-PLCη1) might be enhanced by intracellular calcium mobilization that amplifies the PI-PLCs activity. As for PI-PLCζ, its activation and nuclear translocation mechanisms remain unknown (Fig. 3). Alternative splicing variants have been reported for several of PI-PLC isozymes, including human and rat PI-PLCβ1, human PI-PLCβ2, rat PI-PLCβ4, rat PI-PLCδ4, and human PI-PLCε (47.Peruzzi D. Aluigi M. Manzoli L. Billi A.M. Di Giorgio F.P. Morleo M. Martelli A.M. Cocco L. Molecular characterization of the human PLC beta1 gene.Biochim. Biophys. Acta. 2002; 1584: 46-54Crossref PubMed Scopus (26) Google Scholar, 48.Bahk Y.Y. Song H. Baek S.H. Park B.Y. Kim H. Ryu S.H. Suh P.G. Localization of two forms of phospholipase C-beta1, a and b, in C6Bu-1 cells.Biochim. Biophys. 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Indeed, two splicing variants of the PI-PLCβ1 isozyme have been identified both in rat and mouse, and they differ in their C-terminal sequences (48.Bahk Y.Y. Song H. Baek S.H. Park B.Y. Kim H. Ryu S.H. Suh P.G. Localization of two forms of phospholipase C-beta1, a and b, in C6Bu-1 cells.Biochim. Biophys. Acta. 1998; 1389: 76-80Crossref PubMed Scopus (69) Google Scholar). As for the human PI-PLCβ1 gene, also in this case there are two alternative splicing variants, with PI-PLCβ1a containing a putative nuclear localization sequence and a nuclear export sequence region and PI-PLCβ1b showing only a putative nuclear localization sequence. Therefore, these variants of PI-PLCβ1 may differ in their cellular localization, suggesting that the transit in and out of the nucleus is finely regulated, and possibly hinting at a different role for these two splicing variants (47.Peruzzi D. Aluigi M. Manzoli L. Billi A.M. Di Giorgio F.P. Morleo M. Martelli A.M. Cocco L. Molecular characterization of the human PLC beta1 gene.Biochim. Biophys. Acta. 2002; 1584: 46-54Crossref PubMed Scopus (26) Google Scholar). Also, human PI-PLCβ2 shows two splicing variants: PI-PLCβ2a and PI-PLCβ2b, differing in 15 amino acid residues at the C-terminal region, so that the second transcript variant results in a shorter protein (49.Mao G.F. Kunapuli S.P. Koneti Rao A. Evidence for two alternatively spliced forms of phospholipase C-beta2 in haematopoietic cells.Br. J. Haematol. 2000; 110: 402-408Crossref PubMed Scopus (19) Google Scholar, 53.Sun L. Mao G. Kunapuli S.P. Dhanasekaran D.N. Rao A.K. Alternative splice variants of phospholipase C-beta2 are expressed in platelets: effect on Galphaq-dependent activation and localization.Platelets. 2007; 18: 217-223Crossref PubMed Scopus (14) Google Scholar). Interestingly, several alterative splicing variants of the PI-PLCβ4 gene have been reported: two alternative splicing variants were identified from rat and bovine brain (50.Kim M.J. Min D.S. Ryu S.H. Suh P.G. A cytosolic, galphaq- and betagamma-insensitive splice variant of phospholipase C-beta4.J. Biol. Chem. 1998; 273: 3618-3624Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 54.Min D.S. Kim D.M. Lee Y.H. Seo J. Suh P.G. Ryu S.H. Purification of a novel phospholipase C isozyme from bovine cerebellum.J. Biol. Chem. 1993; 268: 12207-12212Abstract Full Text PDF PubMed Google Scholar), while the third splicing variant of rat PI-PLCβ4 has an additional 37 nucleotide exon at the C-terminal region (55.Adamski F.M. Timms K.M. Shieh B.H. A unique isoform of phospholipase Cbeta4 highly expressed in the cerebellum and eye.Biochim. Biophys. Acta. 1999; 1444: 55-60Crossref PubMed Scopus (23) Google Scholar). In humans there are also three alternative splicing variants of the PI-PLCβ4 gene, so that variant 1 lacks an internal segment and has a longer and distinct C terminus, variant 2 lacks an alternate in-frame exon in the central coding region, and variant 3 represents the longest transcript (55.Adamski F.M. Timms K.M. Shieh B.H. A unique isoform of phospholipase Cbeta4 highly expressed in the cerebellum and eye.Biochim. Biophys. Acta. 1999; 1444: 55-60Crossref PubMed Scopus (23) Google Scholar). Altogether, all PI-PLCβ genes have at least two alternative splicing variants, which differ mostly in their C-terminal sequences and potentially play different roles in cellular processes. Also human PI-PLCγ1 gene has two alternative splicing variants that differ in their C-terminal sequences, but in this case the precise function of the two alternative splicing variants is still unknown (56.Upshaw J.L. Schoon R.A. Dick C.J. Billadeau D.D. Leibson P.J. The isoforms of phospholipase C-gamma are differentially used by distinct human NK activating receptors.J. Immunol. 2005; 175: 213-218Crossref PubMed Scopus (59) Google Scholar). Alternative splicing variants of PI-PLCδ isozymes show several different patterns of splicing variants. Indeed, mouse PI-PLCδ1b differs from PI-PLCδ1a by 274 amino acid residues that extend fro
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