Epac inhibits migration and proliferation of human prostate carcinoma cells

Grandoch, Maria; Rose, Agostino Maria De; Braak, Michael ter; Jendrossek, Verena; Rübben, H.; Fischer, JW; Schmidt, Martina; Weber, Artur‐Aron

doi:10.1038/sj.bjc.6605439

Cited by 55 publications

(56 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Epac itself or together with its target Rap has been implicated in the control of cell proliferation, and another major cAMP target, protein kinase A (PKA), was shown to act synergistically with these proteins in this process in several cases. [52][53][54][55][56][57] Our observation underlines the link between Epac, Rap, PKA and the cell cycle. However, further investigations are needed to determine whether their effects in HUVECs are proliferative or anti-proliferative and Rap-or PKA-dependent.…”

Section: Cid-msa Etd and Hcd Have Complementary Contributions To Phosupporting

confidence: 55%

Quantitative global phosphoproteomics of human umbilical vein endothelial cells after activation of the Rap signaling pathway

et al. 2013

View full text Add to dashboard Cite

The small GTPase Rap1 is required for proper cell-cell junction formation and also plays a key role in mediating cAMP-induced tightening of adherens junctions and subsequent increased barrier function of endothelial cells. To further study how Rap1 controls barrier function, we performed quantitative global phosphoproteomics in human umbilical vein endothelial cells (HUVECs) prior to and after Rap1 activation by the Epac-selective cAMP analog 8-pCPT-2 0 -O-Me-cAMP-AM (007-AM). Tryptic digests were labeled using stable isotope dimethyl labeling, enriched with phosphopeptides by strong cation exchange (SCX), followed by titanium(IV) immobilized metal affinity chromatography (Ti 4+ -IMAC) and analyzed by high resolution mass spectrometry. We identified 19 859 unique phosphopeptides containing 17 278 unique phosphosites on 4594 phosphoproteins, providing the largest HUVEC phosphoproteome to date. Of all identified phosphosites, 220 (B1%) were more than 1.5-fold up-or downregulated upon Rap activation, in two independent experiments. Compatible with the function of Rap1, these alterations were found predominantly in proteins regulating the actin cytoskeleton, cell-cell junctions and cell adhesion.

show abstract

Section: Cid-msa Etd and Hcd Have Complementary Contributions To Phosupporting

confidence: 55%

Quantitative global phosphoproteomics of human umbilical vein endothelial cells after activation of the Rap signaling pathway

et al. 2013

View full text Add to dashboard Cite

show abstract

“…For example, PKA can inhibit Rap1-dependent angiogenesis, acting downstream of Rap1 (40). cAMP-dependent activation of Epac can regulate Rap1-dependent adhesion and migration (27,(41)(42)(43)(44). PKA and other kinases can decrease the signaling actions of Epac by regulating the availability of cAMP through phosphodiesterases (45)(46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase A-dependent Phosphorylation of Rap1 Regulates Its Membrane Localization and Cell Migration

Takahashi

Dillon

Liu

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The small G protein Rap1 is phosphorylated within its carboxyl terminus by the cAMP-dependent protein kinase PKA. Results: This phosphorylation removes Rap1 from the plasma membrane to limit Rap1 signaling. Conclusion: Rap1 phosphorylation switches Rap1 off the membrane and terminates its activation. Significance: Carboxyl-terminal phosphorylation may be common among small G proteins to regulate GTP/GDP cycling and downstream signaling.

show abstract

“…32,33 Rap1, an immediate effector of Epac, has been shown to contribute to Epac-mediated cell migration. 11,27,31,34 In addition, Rap1 has been demonstrated to promote cell migration via regulation of integrin and actin polymerization.…”

Section: Discussionmentioning

confidence: 99%

Epac1 Deficiency Attenuated Vascular Smooth Muscle Cell Migration and Neointimal Formation

Kato

Yokoyama

Yanai

et al. 2015

ATVB

View full text Add to dashboard Cite

Consistent with this evidence, exogenously administered PDGF-BB into the rat carotid artery after endothelial denudation increased neointimal lesions. 2,4 In addition, genetic deletion of PDGFR-β decreased SMC accumulation in atherosclerotic lesions. 2,5 This accumulating evidence suggests that PDGF-BB and PDGFR-β signaling play a prominent role in vascular SMC migration into the neointima after vascular injury and during the development of atherosclerosis. 2It has been suggested that PDGF-BB-mediated cell migration is attributed to the activation of intracellular signal transduction pathways, including phosphatidylinositol 3-kinase, mitogen-activated protein kinase cascade, and © 2015 American Heart Association, Inc. Objective-Vascular smooth muscle cell (SMC) migration causes neointima, which is related to vascular remodeling after mechanical injury and atherosclerosis development. We previously reported that an exchange protein activated by cAMP (Epac) 1 was upregulated in mouse arterial neointima and promoted SMC migration. In this study, we examined the molecular mechanisms of Epac1-induced SMC migration and the effect of Epac1 deficiency on vascular remodeling in vivo. Approach and Results-Platelet-derived growth factor-BB promoted a 2-fold increase in SMC migration in a primary culture of aortic SMCs obtained from Epac1 +/+ mice (Epac1 +/+ -ASMCs), whereas there was only a 1.2-fold increase in Epac1 −/− -ASMCs. The degree of platelet-derived growth factor-BB-induced increase in intracellular Ca 2+ was smaller in Fura2-labeled Epac1 −/− -ASMCs than in Epac1 +/+ -ASMCs. In Epac1 +/+ -ASMCs, an Epac-selective cAMP analog or platelet-derived growth factor-BB increased lamellipodia accompanied by cofilin dephosphorylation, which is induced by Ca 2+ signaling, whereas these effects were rarely observed in Epac1−/− -ASMCs. Furthermore, 4 weeks after femoral artery injury, prominent neointima were formed in Epac1 +/+ mice, whereas neointima formation was significantly attenuated in Epac1 −/− mice in which dephosphorylation of cofilin was inhibited. The chimeric mice generated by bone marrow cell transplantation from Epac1 +/+ into Epac1 −/− mice and vice versa demonstrated that the genetic background of vascular tissues, including SMCs rather than of bone marrow-derived cells affected Epac1-mediated neointima formation. Conclusions-These data suggest that Epac1 deficiency attenuates neointima formation through, at least in part, inhibition of SMC migration, in which a decrease in Ca 2+ influx and a suppression of cofilin-mediated lamellipodia formation occur. 6,7 In addition to these signaling pathways, it has been recognized that PDGF-BB increases intracellular cAMP via a G protein-coupled receptor transactivation mechanism. 8,9 However, the role of PDGF-BB-induced cAMP in SMC migration remains unknown.A major second messenger cAMP activates protein kinase A (PKA) and an exchange protein activated by cAMP (Epac). 10Epac has 2 isoforms, Epac1 and Epac2, both of which are activated in living cells by physiol...

show abstract

Epac inhibits migration and proliferation of human prostate carcinoma cells

Cited by 55 publications

References 28 publications

Quantitative global phosphoproteomics of human umbilical vein endothelial cells after activation of the Rap signaling pathway

Quantitative global phosphoproteomics of human umbilical vein endothelial cells after activation of the Rap signaling pathway

Protein Kinase A-dependent Phosphorylation of Rap1 Regulates Its Membrane Localization and Cell Migration

Epac1 Deficiency Attenuated Vascular Smooth Muscle Cell Migration and Neointimal Formation

Contact Info

Product

Resources

About