Phospholipase Cε Hydrolyzes Perinuclear Phosphatidylinositol 4-Phosphate to Regulate Cardiac Hypertrophy

Zhang, Lianghui; Malik, Sundeep; Pang, Jinjiang; Wang, Huan; Park, Keigan M.; Yule, David I.; Blaxall, Burns C.; Smrcka, Alan V.

doi:10.1016/j.cell.2013.02.047

Cited by 140 publications

(214 citation statements)

References 53 publications

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“…Otherwise, global Plce KO is more susceptible than WT to the development of cardiac hypertrophy and fibrosis after chronic ISO infusion (70). In contrast with global Plce KO, myocyte-specific Plce KO is not susceptible, but is rescued from cardiac hypertrophy as well as cardiac dysfunction after TAC (71). Also, PLCε was demonstrated to generate a multifunctional complex with muscle-specific A-kinase-anchoring protein at or near the nuclear envelope along with Epac1, PKCε, PKD, and RyR2 in cardiac myocytes (71).…”

Section: Discussionmentioning

confidence: 95%

“…In contrast with global Plce KO, myocyte-specific Plce KO is not susceptible, but is rescued from cardiac hypertrophy as well as cardiac dysfunction after TAC (71). Also, PLCε was demonstrated to generate a multifunctional complex with muscle-specific A-kinase-anchoring protein at or near the nuclear envelope along with Epac1, PKCε, PKD, and RyR2 in cardiac myocytes (71). Pkce KO does not show a protective phenotype and is not susceptible to development of cardiac hypertrophy after TAC, in contrast with global Plce KO and myocyte-specific Plce KO (72).…”

Section: Discussionmentioning

confidence: 99%

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Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses

Okumura¹,

Fujita²,

Cai³

et al. 2014

J. Clin. Invest.

100

148

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PKA phosphorylates multiple molecules involved in calcium (Ca 2+ ) handling in cardiac myocytes and is considered to be the predominant regulator of β-adrenergic receptor-mediated enhancement of cardiac contractility; however, recent identification of exchange protein activated by cAMP (EPAC), which is independently activated by cAMP, has challenged this paradigm. Mice lacking Epac1 (Epac1 KO) exhibited decreased cardiac contractility with reduced phospholamban (PLN) phosphorylation at serine-16, the major PKA-mediated phosphorylation site. In Epac1 KO mice, intracellular Ca 2+ storage and the magnitude of Ca 2+ movement were decreased; however, PKA expression remained unchanged, and activation of PKA with isoproterenol improved cardiac contractility. In contrast, direct activation of EPAC in cardiomyocytes led to increased PLN phosphorylation at serine-16, which was dependent on PLC and PKCε. Importantly, Epac1 deletion protected the heart from various stresses, while Epac2 deletion was not protective. Compared with WT mice, aortic banding induced a similar degree of cardiac hypertrophy in Epac1 KO; however, lack of Epac1 prevented subsequent cardiac dysfunction as a result of decreased cardiac myocyte apoptosis and fibrosis. Similarly, Epac1 KO animals showed resistance to isoproterenol-and aging-induced cardiomyopathy and attenuation of arrhythmogenic activity. These data support Epac1 as an important regulator of PKA-independent PLN phosphorylation and indicate that Epac1 regulates cardiac responsiveness to various stresses.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses

Okumura¹,

Fujita²,

Cai³

et al. 2014

J. Clin. Invest.

100

148

View full text Add to dashboard Cite

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“…PLCe1 has been characterized as a direct effector of Ras (13), and recent work has shown a tumor suppressor role for this protein in Rastriggered cancers (20,21). PLCe1 was also shown to modulate adrenergic receptor-dependent cardiac contraction and to inhibit cardiac hypertrophy (22,23). Patients with focal segmental glomerulosclerosis have been found to have loss-of-function mutations in PLCe1, and PLCe1 itself interacts with transient receptor potential channel 6 (24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

Strazza

Azoulay-Alfaguter

Peled

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase Ce 1 (PLCe1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1α)-induced Rap1 activation. We have shown that SDF-1α-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLCe1 was necessary for SDF-1α-induced adhesion using shear stress, cell morphology alterations, and crawling on intercellular adhesion molecule 1 (ICAM-1)-expressing cells. Structurefunction experiments to separate the dual-enzymatic function of PLCe1 uncover necessary contributions of the CDC25, Pleckstrin homology, and Ras-associating domains, but not phospholipase activity, to this pathway. In the mouse model of delayed type hypersensitivity, we have shown an essential role for PLCe1 in T-cell migration to inflamed skin, but not for cytokine secretion and proliferation in regional lymph nodes. Our results reveal a signaling pathway where SDF-1α induces T-cell adhesion through activation of PLCe1, suggesting that PLCe1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs.

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“…129 Likewise, cardiac-specific deletion of PLCε isoform inhibits the development of cardiac hypertrophy after transverse aortic constriction, further substantiating that EPAC1-PLCε pathway promotes hypertrophy. 131 This inositol triphosphate-receptor-dependent nuclear Ca 2+ elevation together with an SR-Ca 2+ leak observed after EPAC stimulation may contribute to activate the 2 key prohypertrophic signaling effectors, calcineurin and CaMKII ( Figure 6). …”

Section: Epac Hypertrophic Signalingmentioning

confidence: 99%

“…Also, EPAC1 is scaffolded at the nuclear envelope with PLCε and to muscle-specific A-kinase anchoring proteins in primary cardiomyocytes. 131 Inositol triphosphate-receptor is a Ca 2+ release channel which can, not only generate a local Ca 2+ signaling effect at the level of the T-tubular-SR junctional complex but also in the perinuclear area of cardiomyocytes, where it has been shown to participate in the excitation-transcription coupling, a process by which local Ca 2+ activates gene transcription. 143 Therefore, this EPAC-PLCε pathway may provide a mechanistic basis for the previous findings that EPAC1 regulates hypertrophic gene expression by activating nuclear CaMKII and subsequent phosphorylation of proteins of the epigenetic machinery, especially histone deacetylases (HDACs) and, in particular, class II HDACs (eg, HDAC4 and 5; Figure 6).…”

Section: Epac Compartmentationmentioning

confidence: 99%

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Lezoualc’h

Fazal

Laudette

et al. 2016

Circulation Research

147

143

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C yclic adenosine 3′,5′-monophosphate (cAMP) is one of the most studied signaling molecules that plays a critical role in cellular responses to extracellular stimuli in the cardiovascular system. It controls a wide range of biological effects, including cell proliferation, differentiation, and apoptosis. 1 cAMP is produced from ATP by transmembrane adenylyl cyclase on activation of Gs-coupled G protein-coupled receptors. 2In addition, soluble adenylyl cyclase is a second intracellular source of cAMP and can be activated by divalent cations in various subcellular compartments.3 The intracellular level of cAMP depends not only on its production by adenylyl cyclase but also its degradation by a large family of cAMP phosphodiesterases (PDEs), which catalyze the hydrolysis of cAMP into 5′-AMP. 4 PDEs are key actors in limiting the spread of cAMP and seem critical for the formation of dynamic microdomains that confer specific response to various hormones. 4 Besides specialized membrane structures that may also limit cAMP diffusion, A-kinase anchoring proteins function to tether cAMP effectors and PDEs enzymes into defined cellular compartments and, therefore, maintain localized pools of cAMP to control the cellular actions of the second messenger. 5Until recently, the intracellular effects of cAMP were attributed to the activation of protein kinase A (PKA) and cyclic nucleotide-gated ion channels. In 1998, a family of novel cAMP effector proteins named exchange proteins directly activated by cAMP (EPACs) was discovered. 6,7 The EPAC protein family is composed of EPAC1 and EPAC2, which act as guanine-nucleotide exchange factors (GEFs) for the small G proteins, Rap1 and Rap2, and function in a PKA-independent manner. 6,7 On binding to cAMP, EPAC promotes the exchange of GDP for GTP, thereby inducing the activation of the small G protein Rap.8 In contrast, Rap-GTPase-activating proteins enhance the intrinsic GTP hydrolysis activity of Rap leading to GTPase inactivation. 9The cycling of Rap between its inactive and active states provides a mechanism to regulate the binding to effector proteins.The discovery of EPAC proteins has broken the dogma surrounding cAMP and PKA, and uncovered new perspectives for the understanding of cAMP signaling in the cardiovascular system. The functions of these cAMP-sensitive GEFs in various subcellular compartments and cellular contexts are currently being unraveled, but given the availability of EPAC-specific ligands and engineered mouse models, a large body of evidence indicates that EPAC proteins are involved in multiple biological actions of cAMP, such as cardiac hypertrophy and vascular inflammation. In this review, after a description of EPAC protein structures and mechanism of activation, we discuss recent advances in the discovery of novel pharmacological modulators of EPAC (Figure 1). We provide an overview of the roles of EPAC proteins, their signalosome and compartmentation in cardiovascular function and diseases. We also discuss the therapeutic potential of EPAC ligands in the t...

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Phospholipase Cε Hydrolyzes Perinuclear Phosphatidylinositol 4-Phosphate to Regulate Cardiac Hypertrophy

Cited by 140 publications

References 53 publications

Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses

Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses

PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

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