The cAMP sensors, EPAC1 and EPAC2, display distinct subcellular distributions despite sharing a common nuclear pore localisation signal

Parnell, Euan; Smith, Brian O.; Yarwood, Stephen J.

doi:10.1016/j.cellsig.2015.02.009

Cited by 34 publications

(55 citation statements)

References 30 publications

(63 reference statements)

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“…8 The CDC25-HD of EPAC1 contains a functional nuclear pore localization signal. 27 The linker region located between the regulatory and the catalytic regions contains the hinge and the lid, which are implicated in the communication between both parts of the protein. 28 In the absence of cAMP, EPAC GEF activity is inhibited because of an intramolecular interaction between its regulatory and catalytic domains, thus preventing the binding of the Rap effector ( Figure 3).…”

Section: Epac Protein Structure and Mechanism Of Activationmentioning

confidence: 99%

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

Lezoualc’h

Fazal

Laudette

et al. 2016

Circulation Research

144

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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Section: Epac Protein Structure and Mechanism Of Activationmentioning

confidence: 99%

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

Lezoualc’h

Fazal

Laudette

et al. 2016

Circulation Research

144

143

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“…The recent identification of the sequence in the CDC25-HD domain of Epac1 responsible for the binding [28] provided us with a tool to study the role of Epac1 localization to the nuclear pore in PGE 2 -induced activation of β-catenin. In this study we were able to show that blocking Epac1 localization to the nuclear pore, using an Epac1 mutant that lacks this sequence [28], abolished PGE 2 -induced activation of β-catenin-dependent transcription. Studies on the activity of Epac1 binding to RanBP2 have provided contradictory results.…”

Section: Discussionmentioning

confidence: 99%

“…Studies on the activity of Epac1 binding to RanBP2 have provided contradictory results. One study showed decreased activity [28], while another showed increased activity [26]. Thus, the exact role of Epac1 at the nuclear envelope or nuclear pore is still controversial and warrants further exploration.…”

Section: Discussionmentioning

confidence: 99%

Epac1 links prostaglandin E2 to β-catenin-dependent transcription during epithelial-to-mesenchymal transition

et al. 2016

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In epithelial cells, β-catenin is localized at cell-cell junctions where it stabilizes adherens junctions. When these junctions are disrupted, β-catenin can translocate to the nucleus where it functions as a transcriptional cofactor. Recent research has indicated that PGE2 enhances the nuclear function of β-catenin through cyclic AMP. Here, we aim to study the role of the cyclic AMP effector Epac in β-catenin activation by PGE2 in non-small cell lung carcinoma cells.We show that PGE2 induces a down-regulation of E-cadherin, promotes cell migration and enhances β-catenin translocation to the nucleus. This results in β-catenin-dependent gene transcription. We also observed increased expression of Epac1. Inhibition of Epac1 activity using the CE3F4 compound or Epac1 siRNA abolished the effects of PGE2 on β-catenin. Further, we observed that Epac1 and β-catenin associate together. Expression of an Epac1 mutant with a deletion in the nuclear pore localization sequence prevents this association. Furthermore, the scaffold protein Ezrin was shown to be required to link Epac1 to β-catenin.This study indicates a novel role for Epac1 in PGE2-induced EMT and subsequent activation of β-catenin.

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“…In nonexcitable cells, ADCY8 is predominantly stimulated by Ca 2+ ions entering the cells via capacitative calcium entry, a mechanism triggered by depletion of intracellular Ca 2+ stores [25]. Moreover, CNBD1 (cyclic nucleotidebinding domaincontaining protein 1) was also upregulated in the second heat map [26]. Further studies will be necessary to establish whether increased expression of this domain is an indication of cAMP production by ADCY8 or whether CaSR might couple to G s in this cellular context.…”

Section: Discussionmentioning

confidence: 99%

Cinacalcet inhibits neuroblastoma tumor growth and upregulates cancer-testis antigens

Torres¹,

Rodríguez-Hernández²,

Garcia³

et al. 2016

European Journal of Cancer

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The cAMP sensors, EPAC1 and EPAC2, display distinct subcellular distributions despite sharing a common nuclear pore localisation signal

Cited by 34 publications

References 30 publications

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

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

Epac1 links prostaglandin E2 to β-catenin-dependent transcription during epithelial-to-mesenchymal transition

Cinacalcet inhibits neuroblastoma tumor growth and upregulates cancer-testis antigens

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