The physiological roles of primary phospholipase C

Advances in Biological Regulation 53 (2013) 232–241

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The physiological roles of primary phospholipase C Yong Ryoul Yang a, Matilde Y. Follo b, Lucio Cocco b, Pann-Ghill Suh a, * a

School of Nano-Biotechnology and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy b

a b s t r a c t The roles of phosphoinositide-specific phospholipase C (PLC) have been extensively investigated in diverse cell lines and pathological conditions. Among the PLC isozmes, primary PLCs, PLC-b and PLCg, are directly activated by receptor activation, unlike other secondary PLCs (PLC-3, PLC-d1, and PLC-h1). PLC-b isozymes are activated by G protein couple receptor and PLC-g isozymes are activated by receptor tyrosine kinase (RTK). Primary PLCs are differentially expressed in different tissues, suggesting their specific roles in diverse tissues and regulate a variety of physiological and pathophysiological functions. Thus, dysregulation of phospholipases contributes to a number of human diseases and primary PLCs have been identified as therapeutic targets for prevention and treatment of diseases. Here we review the roles of primary PLCs in physiology and their impact in pathology. Ó 2012 Published by Elsevier Ltd.

Introduction Characteristics of phospholipase C Phosphoinositide-specific phospholipase C (PLC) hydrolyzes phosphatidylinositol-4,5-bisphosphate (PIP2) to produce inositol-1,4, 5-triphosphate(IP3) and diacylglycerol (DAG) in the cellular * Corresponding author. Tel.: þ82 52 217 2621; fax: þ82 52 217 2609. E-mail address: [email protected] (P.-G. Suh). 2212-4926/$ – see front matter Ó 2012 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.jbior.2013.08.003

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setting of ligand-mediated signal transduction (Fig. 1). DAG activates protein kinase C (PKC), while binding of IP3 to its receptor triggers the release of calcium ions from intracellular stores. The first evidence of PLC activity was suggested by Hokin et al., in 1953 who reported specific hydrolysis of phospholipids in pigeon pancreas slices after cholinergic stimulation (Hokin and Hokin, 1953). In 1983, Sterb et al.demonstrated that IP3 generated from PIP2 hydrolysis is responsible for mobilization of intracellular calcium in pancreatic acinar cells (Streb et al., 1983). To date, 13 mammal PLC isozymes have been identified and are divided into six subtypes: PLCb(14), g(1,2), d(1,3,4), 3, z and h (1,2). Highly conserved regions in PLC isozymes include the catalytic X and Y domains, as well as diverse regulatory domains, including the C2 domain, the EF-hand motif and the pleckstrin homology (PH) domain. Notably, each PLC subtype has a unique domain and PLC isozymes are differentially expressed in different tissues. These factors contribute to the specific regulatory mechanisms and functional diversity of PLC isozymes (Rhee, 2001). PLC-b subtypes are activated by G-protein coupled receptor (GPCR) through several mechanisms. In contrast, PLC-g subtypes are activated by receptor tyrosine kinase (RTK). Upon growth factor stimulation, PLC-g is recruited to activated growth factor receptors via SH2 domain-phosphotyrosine interaction and is then subjected to phosphorylation by RTK (Rhee, 2001). On the other hand, PLC-3 can be activated by both GPCR and RTK activation with distinct activation mechanisms (Smrcka et al., 2012). It has been hypothesized that the overall PLC activity may be amplified and sustained by both intracellular calcium mobilization and extracellular calcium entry. Several studies have also suggested a positive feedback amplification of PLC signaling (Okubo et al., 2001; Thore et al., 2005, 2004; Young et al., 2003). PLC-d1 and PLC-h1 are activated by via GPCRmediated calcium mobilization and involved in positive feedback signal amplification of PLC (Kim et al., 2011, 1999).

Fig. 1. Schematic illustration of the primary and secondary PLC signal network Diverse extracellular ligands activate specific receptors, such as G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). Primary phospholipase C-b (PLC-b) is activated by the Ga or Gbg subunit. In RTK signaling, RTKs directly recruit and activate primary PLC-g. Secondary PLC-3 is stimulated by a small GTPase (RAP2B or RHOA). Secondary PLC-d and PLC-h are activated by calcium. Activated PLCs hydrolyze phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to generate 2 s messengers, diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). DAG activates protein kinase C (PKC) and IP3 induces calcium release from the endoplasmic reticulum.

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By these mechanisms, it has been suggested that PLC-b and PLC-g (primary PLC) are primarily activated by extracellular stimuli and PLC-3 (secondary PLC) is secondarily activated by Rho and Ras GTPases. Activation of PLC-d1 and PLC-h1 (secondary PLC) might be secondarily enhanced by intracellular calcium mobilization to amplify PLCs activity. The activation mechanism for PLC-z remains to be revealed (Fig. 1). Physiological functions of primary PLC (b and g) Primary PLCs have a unique domain and PLC isozymes are differentially distributed in different tissues. The specific characteristics of primary PLCs are reflected by their physiological and pathophysiological roles in diverse tissues, each PLC isozyme is strongly linked to diverse human diseases (Table 1). Brain disorders Hormones and neurotransmitters activate PLC isozymes through GPCR in the brain, indicating that PLC isozymes regulate diverse brain functions. Each PLC isozyme selectively couples to specific neurotransmitter receptors in different regions of the brain, contributing to specific functions. PLC-b1 is highly expressed in the brain, including the cerebral cortex, hippocampus, amygdala, lateral septum and olfactory bulb (Ross et al., 1989; Takenawa et al., 1991) and regulates cortical development and synaptic plasticity by modulating hippocampal muscarinic acetylcholine receptor signaling (Hannan et al., 1998; Spires et al., 2005). Consistent with this, PLC-b1 knock-out mice showed epilepsy (Kim et al., 1997) and abnormal behaviors due to excessive neurogenesis and aberrant migration of adult-born neurons (Choi et al., 1989; Wallace and Claro, 1990). Interestingly, a PLC-b1 mutation in human patients has been observed, and genetic studies revealed that the PLC-b1 mutation Table 1 Summary of primary PLC roles in physiology. PLC isozyme

Analysis system

Disease

PLC-b1

Knock-out mice Genetic studies

PLC-b2

PLC-b3

Expression level of patient sample Human breast cancer-derived cells Expression level of patient sample Knock-out mice

Epilepsy Early-onset epileptic encephalopathy Schizophrenia Bipolar disorder Myelodysplastic syndromes Breast cancer

PLC-b4

Knock-out mice Knock-out mice

PLC-g1

PLC-g2

Knock-in mice R6/1 HD model mice Anti-depressant drug effect on cultured cortical cells Expression level of patient sample Mice model of metastasis T-cell specific Knock-out mice LATY136F Knock-in mice Genetic studies Chimeric Knock-out mice Genetic studies Knock-out mice

Acute promyelocytic leukemia Myeloproliferative disease (lymphoma) Atherosclerosis Ataxia Absence seizure Visual processing defect Epilepsy Huntington’s disease Depression Breast cancer Colon cancer Breast cancer metastasis Autoimmune disease Metabolic syndrome Multicystic kidney Cold urticarial and immune dysregulation Arthritis

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is closely linked to early-onset epileptic encephalopathy (Kurian et al., 2010). Furthermore, deletion of PLC-b1 gene was observed in orbito-frontal cortex samples in patients with schizophrenia and bipolar disorder (Lo Vasco et al., 2012; Lo Vasco et al., 2013). PLC-g1 is highly expressed in a broad range of brain regions and participates in various neuronal events, such as neurite outgrowth, neuronal cell migration and synaptic plasticity through the Trk receptor (Minichiello, 2009; Park and Poo, 2013). The pathological relevance of PLC-g1 has been suggested in epilepsy, Huntington’s disease (HD), depression, Alzheimer’s disease (AD) and bipolar disorder (Jang et al., 2013). Moreover, systemic administration of pilocarpine induces status epilepticus and increases tyrosine phosphorylation of PLC-g1 (He et al., 2010). Consistent with this, epilepsy is markedly inhibited in trkBPLC/PLC knock-in mice lacking PLCg-1docking sites in TrkB (He et al., 2010). On the other hand, phosphorylation of PLC-g1 is decreased in HD models (Giralt et al., 2009), and the expression levels of BDNF and TrkB are reduced in humans and mice with HD (Ferrer et al., 2000; Gines et al., 2006; Zuccato et al., 2008). Moreover, activation of PLC-g1 induces activation of CREB, which is required to increase BDNF, for a long-term anti-depressive effect in the hippocampus (Minichiello et al., 2002; Nestler et al., 2002; Yagasaki et al., 2006). Tumorigenesis and metastasis PLCs are activated by a variety of extracellular ligands, such as growth factors, hormones, cytokines and lipids. Activation of PLCs is involved in tumorigenesis and/or metastasis linked to migration, proliferation, growth, inflammation, angiogenesis and actin cytoskeleton reorganization. Therefore, aberrant expression and activity of PLC isozymes is detected in a variety of human cancers and is associated with tumor progression. PLC-b2 is highly up-regulated in breast tumors and correlates with poor clinical outcome, suggesting its role as a marker for breast cancer severity (Bertagnolo et al., 2006), as PLC-b2 is important for migration of breast cancer-derived cell lines and mitosis of breast-derived tumor cells (Bertagnolo et al., 2007). In addition to PLC-b2, also PLC-g1 level is increased in cancers as compared to normal tissues (Arteaga et al., 1991; Noh et al., 1994), and it was suggested that PLC-g1 is required for cell migration and needed for tumor cell invasiveness and metastasis, both in vitro and in vivo. Indeed, PLC-g1 appears to be at the convergence point for various signaling pathways that activate cell spreading and migration mediated by integrins (Katan et al., 2005). Consistent with these data, downregulation of PLC-g1 expression inhibited Rac1 activation and resulted in suppression of human MDA-MB-231 breast cancer cell-derived lung metastasis in an in vivo mouse model (Falasca et al., 2008). In addition to mediating the effects of adhesion receptors on cell motility, PLC-g1 has been shown to mediate the cell motility effects of growth factors, including platelet-derived growth factor (PDGF) (Kundra et al., 1994), epithermal growth factor (EGF) (Chen et al., 1994; Xie et al., 2010), insulin-like growth factor (IGF) (Bornfeldt et al., 1994) and hepatocyte growth factor (HGF) (Derman et al., 1996; Martin et al., 2008). Moreover, phosphoinositide 3-kinase (PI3K)-mediated PLC-g1 activation is required for EGF-induced migration of breast cancer cells (Piccolo et al., 2002; Shien et al., 2004). In fact, interactions between the SH3 domain of PLCg1 and Rac1 play a significant role in EGF-induced F-actin formation and cell migration (Li et al., 2009). In vivo mouse models showed the critical role of PLC-g1 in metastasis. In transgenic mice carrying an inducible PLC-g1 gene fragment, a fragment of dominant-negative PLC-g1 limited the metastatic potential of carcinomas in oncogene-induced mammary and prostate cancer tissues (Shepard et al., 2007), strongly suggesting that PLC-g1 is a potential therapeutic target for the clinical treatment of tumor metastasis. Also PLC-b3 is suggested to be a tumor suppressor. In fact, PLC-b3 Knock-Out mice can develop myeloproliferative diseases, lymphoma and other tumors, resulting from an impaired Stat5suppressive mechanism. Furthermore, PLC-b3 is down-regulated in leukocytes of patients with chronic lymphocytic leukemia (Xiao et al., 2009) Myogenesis and adipogenesis PLC-b1 gene exists as alternatively spliced variants b1a and b1b, which differ in their C-terminal residues (Peruzzi et al., 2002). The different localization could denote a different physiological role for

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PLC-b1, in normal cell proliferation or differentiation (Faenza et al., 2005; Martelli et al., 2005; Ramazzotti et al., 2011), which could result in a different role in pathogenesis. Skeletal muscle differentiation is characterized by terminal withdrawal from cell cycle, activation of muscle-specific genes and morphological changes, including myoblast alignment, elongation and fusion of mononucleated myotubes. These events are coordinated by a family of four muscle-specific basic helix-loop-helix transcription factors: MyoD1, Myf5, myogenin, and Mrf4, termed as the muscle regulatory factors (Lassar et al., 1994). C2C12 muscle cell line contains at least three PLC-b isoforms: PLC-b1, PLC-b3 and PLC-b4 (Faenza et al., 2004). Differentiation of C2C12 mouse myoblasts in response to insulin stimulation has been associated with a marked increase of nuclear PLC-b1, whilst PLC-b4 expression decreased in both the cytoplasmic and the perinuclear compartments. Interestingly, an imbalance of nuclear and cytoplasmic PLC-b1 has been correlated to a down-regulation of myogenesis, as evidenced by the over-expression of a cytoplasmic PLC-b1 mutant that, because of the lack of a nuclear localization sequence, acts as a dominant negative and suppresses the differentiation of C2C12 myoblasts (Faenza et al., 2003). Furthermore, recent studies demonstrated that the catalytic activity of PLC-b1 is essential for the transduction of myogenic differentiation signals, through the activation of cjun/AP1 transcription factor (Ramazzotti et al., 2008). During the differentiation of myoblasts to myotubes, nuclear PLC-b1 activates cyclin D3 promoter which, in turn, plays a critical role in the MyoD-mediated arrest of cell cycle, which precedes myoblast differentiation. Therefore, PLC-b1 is a crucial regulator of the skeletal muscle differentiation program, by regulating cyclin D3. These findings, obtained mostly by in vitro studies, resulted to have a great impact in pathophysiology, as the deregulation PLC-b1/cyclin D3 signaling has been associated also with myogenic diseases. In fact, it was recently shown that the modulation of PLC-b1 and cyclin D3 is able to promote the correct myogenic differentiation process, leading to a recovery of myogenin and desmin levels in Myotonic Dystrophy (DM), which is the most prevalent form of muscular dystrophy in adults and is inherited as DM type 1 (DM1) or type 2 (DM2). In particular, it has been shown that the myogenesis of DM cells is characterized by a strong aberration of PI-PLCb1/cyclin D3 signaling (Faenza et al., 2012), as PLCb1 mRNA was expressed at high levels in DM1 and DM2 proliferating myoblasts, as compared with normal human myoblasts. This was not confirmed by protein levels, quantified by Western Blot analyses, thus leading us to hypothesize that there was either a problem at the translational level or an alteration in one of the pathways that process the protein, which is typical of DMs. In fact, the accumulation of aberrant RNA in the nucleus can lead to a blockage of the normal processes involved in translation. On the other hand, also cyclin D3 was low in DM1 differentiating cells, and this could be a critical event leading to impaired myoblast fusion, as cyclin D3 plays a critical role in the Myo-D-mediated arrest of the cell cycle preceding myoblast differentiation. Nuclear PLCb1/cyclin D3 signaling is also required for adipocyte differentiation, where PLC-b1 is upregulated (O’Carroll et al., 2009). Indeed, during 3T3-L1 adipocyte differentiation there are two phases of PLC-b1 activity: the first occurs within 5 min of treatment with differentiation media, does not require new PLC-b1 to enter the nucleus and is regulated by pERK and PKCa. On the other hand, the second phase occurs from day 2 of differentiation, requires new PLC-b1 protein to enter the nucleus and is independent of regulation by pERK and PKCa. Over-expression with PLC mutants, lacking the ERK phosphorylation site or the nuclear localization sequence, revealed that both phases of PLC-b1 activity are required for terminal adipogenic differentiation. Hematopoietic system In the hematopoietic system, nuclear PLC-b1 is associated with differentiation and proliferation. In fact, nuclear PLC-b1 is down-regulated during DMSO-induced differentiation of Friend erythroleukemia cells, so that a higher level of PLC-b1 is essential for maintaining the undifferentiated state of these cells (Martelli et al., 1994; Matteucci et al., 1998). Moreover, the expression of the transcription factor p45/NFE2, a prerequisite for the erythroid differentiation of Friend erythroleukemia cells, is decreased by overexpression of nuclear PLC-b1 (Faenza et al., 2002). Nuclear PLC-b1 has also been associated with cell cycle. In fact, it has been reported that MAPKs, in particular JNK and ERK1/2, play a critical role in transducing the mitogenic stimulus, and that nuclear PLC-b1 is activated during the G2/M phase, along with the recruitment of PKC-a/PKCbI to the nuclear

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compartment (Fiume et al., 2009). Indeed, by means of specific inhibitors of PKCa or PKCbI and by siRNA silencing, our research group provided evidence that, in the nucleus of Friend erythroleukemia cells, PKCa phosphorylates and physically interacts with lamin B1, thus enabling cell cycle progression. Evidence for co-localization rested on two lines of evidence. First, immunocytochemical analysis at TEM showed that PLC-b1 and lamin B1 were in close juxtaposition. In particular, in proliferating cells, both proteins predominantly decorated regions of euchromatin and, to a lesser extent, heterochromatin. Moreover, in G2/M cells both proteins localized in close juxtaposition, decorated predominantly chromosomal structures and, at a low frequency, spaces among chromosomes. Finally, coimmunoprecipitation studies provided evidence that lamin B1 was co-immunoprecipitated with PLC-b1 and vice versa, arguing in favor of a physical interaction. Another work reinforcing the contention that nuclear PLC-b1 constitutes a key step in hematopoiesis emerged by microarray experiments, where an up-modulation of CD24 in cells overexpressing PLC-b1 in the nucleus was observed (Fiume et al., 2005). CD24 is an antigen involved in differentiation and hematopoiesis, is considered as a critical molecule in the metastasizing ability of solid tumors and is over-expressed in a number of leukemias. The modulation of PLC-b1 at a nuclear level is implicated in the pathophysiology of myelodysplastic syndromes (MDS) and could play a role in inducing both myeloid and erythroid differentiation in this disease (Follo et al., 2012a, 2010; 2012c; Mongiorgi et al., 2012). The MDS are a heterogeneous group of bone marrow disorders characterized by an impaired stem cell differentiation leading to a progressive cytopenia and an increased although variable risk of evolution to acute myeloid leukemia (AML). Recently, it has been demonstrated that azacitidine, a demethylating agent currently used in MDS therapy to promote myeloid differentiation, specifically targets PLC-b1. In fact, PLC-b1 promoter methylation and gene expression were quantified in high-risk and low-risk MDS patients during azacitidine administration and compared to the expression of patients treated with only best supportive care, as well as healthy subjects (Fili et al., 2013; Follo et al., 2009, 2011). Interestingly, promoter methylation and gene expression had an opposite trend, with PLC-b1 mRNA levels following and anticipating the clinical outcome, as the variations in PLC-b1 expression, increase or decrease, were detectable prior to the clinical improvement or worsening, respectively. Being azacitidine a demethylating agent, we also analyzed the functional effect of this drug on the structure of PLC-b1 promoter (Follo et al., 2012d). As azacitidine targets one specific CpG Island of the PLC-b1 promoter, we selected four transcription factors spanning over this region. Interestingly, two of them (Sp1 and CEBPa) are mainly involved in the regulation of gene expression but, more importantly, the other two (c-myb and MZF-1) are typically linked to the hematopoietic system. In fact, c-myb is required for regulating the proliferation and survival of normal myeloid progenitors and leukemic blast cells, while MZF-1 is usually associated with the differentiation of the hematopoietic stem cells (Lidonnici et al., 2008; Morris et al., 1995). Our chromatin immunoprecipitation experiments showed that the four selected transcription factors were only partially recruited to PLC-b1 promoter before the start of epigenetic therapy. On the other hand, and specifically in MDS patients responding to azacitidine therapy, the recruitment of three of the four transcription factors (Sp1, CEBPa and MZF-1) increased during hypomethylating treatment. In contrast, even after azacitidine exposure, c-myb showed a low recruitment to PLC-b1 promoter. Considering the role of MZF-1 in myeloid differentiation and the association of c-myb with hematopoietic stem cell proliferation, these results confirm the involvement of PLC-b1 in epigenetic mechanisms, and are particularly consistent with the hypothesis of a contribution of PLC-b1 in azacitidineinduced myeloid differentiation. Interestingly, other studies showed that, after azacitidine treatment, an increase in PLC-b1 levels was followed by a reduction in activated Akt levels, thus indicating that PLC-b1 and Akt could play opposite roles (Follo et al., 2008). This is important, given that Akt not only is associated with leukemogenesis (Martelli et al., 2011, 2012), but also with erytroid differentiation, along with PLC-b1. In fact, not only PLC-b1 has been associated with myeloid differentiation in MDS, but also with erythroid lineage (Follo et al., 2013). In particular, the effect of erythropoietin (EPO) treatment on Akt activation and PLC-b1 expression strengthens the contention that a correct nuclear lipid signaling is essential for erythropoiesis and, more in general, for physiological processes such as cell growth and differentiation(Follo et al., 2012b). In that study, EPO responder patients showed an activation of Akt, as expected, whereas the same cases displayed a PLC-b1 decrease. Interestingly, the

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decrease of PLC-b1 was statistically significant after 4–6 months of therapy, which is consistent with previous findings showing that PLC-b1, after an early transient increase, is down-regulated in primary human erythroblasts treated with EPO for up to 96 h (di Giacomo et al., 2005), therefore suggesting that PLC-b1 could be required at the beginning of erythroid differentiation but is dispensable, if not inhibitory, at later stages. At the same time, also the Akt phosphorylation that we detected in EPO responder cases is in agreement with other previous in vitro studies showing that EPO can induce a nuclear translocation of active Akt, which is required for erythroid differentiation (Missiroli et al., 2009). Immune system dysfunction PLC-g isozymes are essential for B and T cell development and immune responses, and PLC-g1 is essential for T cell receptor signaling, as second messengers generated by PLC-g1, DAG and IP3 mediate activation of NF-kB, Ras-ERK and NFAT signaling in T cells (Ebinu et al., 2000; Lin and Wang, 2004; Rao et al., 1997). Linker for activation of T cells (LAT), a scaffold adaptor protein, mediates T cell signaling and development (Wange, 2000). Y136 in mouse LAT is a binding site for PLC-g1. Mutation of Y136 results in a partial block in early T cell development, with a polyclonal lymphoproliferative disorder and signs of autoimmune disease at around the age of weaning (Sommers, 2002). In addition, a severe defect in positive and negative thymocyte selection was observed in LATY136F knock-in mice, implying that aberrant negative selection might contribute to the proliferation of autoreactive T cells due to a skewed TCR repertoire (Samelson et al., 2005). Moreover, T-cell specific PLC-g1 knock-out mice exhibited impaired T cell development and function and developed inflammatory/autoimmune disease (Wen et al., 2010). Also, PLC-g2 is highly expressed in hematopoietic lineage cells and plays a crucial role in immune responses (Homma et al., 1989; Kurosaki et al., 2000; Kurosaki and Okada, 2001). As expected, PLC-g2 knock-out mice exhibited defects in B cell functions and Fc receptor-mediated signaling (Hashimoto et al., 2000; Ihle et al., 2000). Significantly, whole-exome sequencing of a family affected by dominantly inherited inflammatory disease identified p.Ser707Tyr substitution in the PLC-g2 SH2 domain, which is essential for PLC-g2 activation. Consistent with these data, overexpression of the p.Ser707Tyr mutant, PLC-g2, in leukocytes resulted in elevated PLC-g2 activity (Zhou et al., 2012). Additionally, genetic studies reported that the in-frame deletion of PLC-g2 resulted in constitutive forms of PLC-g2 in individuals with cold urticarial and immune dysregulation. Conflict of interest I don’t have conflict of interest with a submission. Acknowledgements This work was supported by Italian MIUR-FIRB Accordi di Programma 2010 and Celgene Corp and the National Research Foundation of Korea Grant funded by the Korean Government (KRF-2007-341-C00027). References Arteaga CL, Johnson MD, Todderud G, Coffey RJ, Carpenter G, Page DL. Elevated content of the tyrosine kinase substrate phospholipase c-gamma-1 in primary human breast carcinomas. P Natl Acad Sci USA 1991;88:10435–9. Bertagnolo V, Benedusi M, Brugnoli F, Lanuti P, Marchisio M, Querzoli P, et al. Phospholipase C-beta 2 promotes mitosis and migration of human breast cancer-derived cells. Carcinogenesis 2007;28:1638–45. Bertagnolo V, Benedusi M, Querzoli P, Pedriali M, Magri E, Brugnoli F, et al. PLC-beta2 is highly expressed in breast cancer and is associated with a poor outcome: a study on tissue microarrays. Int J Oncol 2006;28:863–72. Bornfeldt KE, Raines EW, Nakano T, Graves LM, Krebs EG, Ross R. Insulin-like growth factor-I and platelet-derived growth factorBB induce directed migration of human arterial smooth muscle cells via signaling pathways that are distinct from those of proliferation. J Clin Invest 1994;93:1266–74. Chen P, Xie H, Sekar MC, Gupta K, Wells A. Epidermal growth factor receptor-mediated cell motility: phospholipase C activity is required, but mitogen-activated protein kinase activity is not sufficient for induced cell movement. J Cell Biol 1994;127:847–57.

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