Epac: Defining a new mechanism for cAMP action

Annual Review of Pharmacology and Toxicology

Volumn 50, Issue , 2010, Pages 355-375

  Gloerich, Martijn ^a   Bos, Johannes L ^a  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

Author keywords

O Me cAMP; 8 pCPT 2 ; CAMP GEF; G protein; Guanine nucleotide exchange factor; Rap

Indexed keywords

CYCLIC AMP; CYCLIC AMP DEPENDENT PROTEIN KINASE; CYCLIC NUCLEOTIDE GATED CHANNEL; EXCHANGE PROTEIN DIRECTLY ACTIVATED BY CAMP; GUANINE NUCLEOTIDE BINDING PROTEIN; GUANINE NUCLEOTIDE EXCHANGE FACTOR; INTEGRIN; ION CHANNEL; MITOGEN ACTIVATED PROTEIN KINASE; PROTEIN; RAP PROTEIN; UNCLASSIFIED DRUG; BETA ADRENERGIC RECEPTOR; CALCIUM; GLUCAGON LIKE PEPTIDE 1; INSULIN; RAPGEF3 PROTEIN, HUMAN;

AMINO TERMINAL SEQUENCE; BLOOD VESSEL PERMEABILITY; CELL MEMBRANE; ENZYME ACTIVATION; ENZYME ACTIVITY; HEART CONTRACTION; HEART VENTRICLE HYPERTROPHY; HORMONE RESPONSE; HUMAN; INFLAMMATION; INSULIN RELEASE; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN TARGETING; RENAL SYSTEM PARAMETERS; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; CAPILLARY PERMEABILITY; DRUG POTENTIATION; KIDNEY; METABOLISM; NERVE CELL; PHYSIOLOGY; SECRETION;

ANIMALS; CALCIUM; CAPILLARY PERMEABILITY; CYCLIC AMP; CYCLIC AMP-DEPENDENT PROTEIN KINASES; GLUCAGON-LIKE PEPTIDE 1; GUANINE NUCLEOTIDE EXCHANGE FACTORS; HUMANS; INFLAMMATION; INSULIN; KIDNEY; NEURONS; RECEPTORS, ADRENERGIC, BETA;

EID: 77949538387     PISSN: 03621642     EISSN: 15454304     Source Type: Book Series    
DOI: 10.1146/annurev.pharmtox.010909.105714     Document Type: Review

References (139)

1. de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, et al. 1998. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 396:474-477
2. Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, et al. 1998. A family of cAMP-binding proteins that directly activate Rap1. Science 282:2275-2279
3. de Rooij J, Rehmann H, van Triest M, Cool RH, Wittinghofer A, Bos JL. 2000. Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs. J. Biol. Chem. 275:20829-20836
4. KilpinenS, Autio R, OjalaK, IljinK, BucherE, et al. 2008. Systematic bioinformatic analysisof expression levels of 17330 human genes across 9783 samples from 175 types of healthy and pathological tissues. Genome Biol. 9:R139
5. Kitayama H, Sugimoto Y, Matsuzaki T, Ikawa Y, Noda M. 1989. A Ras-related gene with transformation suppressor activity. Cell 56:77-84
6. Chrzanowska-Wodnicka M, Smyth SS, Schoenwaelder SM, Fischer TH, White GC 2nd. 2005. Rap1b is required for normal platelet function and hemostasis in mice. J. Clin. Investig. 115:680-687
7. Knox AL, Brown NH. 2002. Rap1 GTPase regulation of adherens junction positioning and cell adhesion. Science 295:1285-1288
8. Ohba Y, Ikuta K, Ogura A, Matsuda J, Mochizuki N, et al. 2001. Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis. EMBO J. 20:3333-3341
9. Crittenden JR, Bergmeier W, Zhang Y, Piffath CL, Liang Y, et al. 2004. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat. Med. 10:982-986 (Pubitemid 39273740)
10. Duchniewicz M, Zemojtel T, Kolanczyk M, Grossmann S, Scheele JS, Zwartkruis FJ. 2006. Rap1A-deficient T and B cells show impaired integrin-mediated cell adhesion. Mol. Cell Biol. 26:643-653
11. Pellis-van Berkel W, Verheijen MH, Cuppen E, Asahina M, de Rooij J, et al. 2005. Requirement of the Caenorhabditis elegans RapGEF pxf-1 and rap-1 for epithelial integrity. Mol. Biol. Cell 16:106-116
12. Raaijmakers JH, Bos JL. 2008. Specificity in Ras and Rap signaling. J. Biol. Chem. 284:10995-10999
13. Rehmann H, Arias-Palomo E, Hadders MA, Schwede F, Llorca O, Bos JL. 2008. Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B. Nature 455:124-127
14. Rehmann H, Das J, Knipscheer P, Wittinghofer A, Bos JL. 2006. Structure of the cyclic-AMP-responsive exchange factor Epac2 in its auto-inhibited state. Nature 439:625-628
15. Poppe H, Rybalkin SD, Rehmann H, Hinds TR, Tang XB, et al. 2008. Cyclic nucleotide analogs as probes of signaling pathways. Nat. Methods 5:277-278
16. Enserink JM, Christensen AE, de Rooij J, van Triest M, Schwede F, et al. 2002. A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Nat. Cell Biol. 4:901-906
17. Rehmann H, Schwede F, Doskeland SO, Wittinghofer A, Bos JL. 2003. Ligand-mediated activation of the cAMP-responsive guanine nucleotide exchange factor Epac. J. Biol. Chem. 278:38548-38556
18. Vliem MJ, Ponsioen B, Schwede F, Pannekoek WJ, Riedl J, et al. 2008. 8-pCPT-2'-O-Me-cAMP-AM: an improved Epac-selective cAMP analogue. ChemBioChem 9:2052-2054
19. Enyeart JA, Enyeart JJ. 2009. Metabolites of an Epac-selective cAMP analog induce cortisol synthesis by adrenocortical cells through a cAMP-independent pathway. PLoS ONE 4:e6088
20. Zhong N, Zucker RS. 2005. cAMP acts on exchange protein activated by cAMP/cAMP-regulated guanine nucleotide exchange protein to regulate transmitter release at the crayfish neuromuscular junction. J. Neurosci. 25:208-214
21. Baillie GS. 2009. Compartmentalized signaling: spatial regulation of cAMP by the action of compartmentalized phosphodiesterases. FEBSJ. 276:1790-1799
22. Beene DL, Scott JD. 2007. A-kinase anchoring proteins take shape. Curr. Opin. Cell Biol. 19:192-198
23. Ponsioen B, GloerichM, RitsmaL, Rehmann H, Bos JL, Jalink K. 2009. Direct spatial control ofEpac1 by cAMP. Mol. Cell Biol. 29:2521-2531
24. Ohba Y, Kurokawa K, Matsuda M. 2003. Mechanism of the spatio-temporal regulation of Ras and Rap1. EMBOJ. 22:859-869
25. Li Y, Asuri S, Rebhun JF, Castro AF, Paranavitana NC, Quilliam LA. 2006. The RAP1 guanine nucleotide exchange factor Epac2 couples cyclic AMP and Ras signals at the plasma membrane. J. Biol. Chem. 281:2506-2514
26. Liu C, Takahashi M, Li Y, Song S, Dillon TJ, et al. 2008. Ras is required for the cyclic AMP-dependent activation of Rap1 via Epac2. Mol. Cell Biol. 28:7109-7125
27. Niimura M, Miki T, Shibasaki T, Fujimoto W, Iwanaga T, Seino S. 2009. Critical role of the N-terminal cyclic AMP-binding domain of Epac2 in its subcellular localization and function. J. Cell Physiol. 219:652-658
28. Qiao J, Mei FC, Popov VL, Vergara LA, Cheng X. 2002. Cell cycle-dependent subcellular localization of exchange factor directly activated by cAMP. J. Biol. Chem. 277:26581-26586
29. Huston E, Lynch MJ, Mohamed A, Collins DM, Hill EV, et al. 2008. EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation. Proc. Natl. Acad. Sci. USA 105:12791-12796
30. Sehrawat S, Cullere X, Patel S, Italiano J, Jr, Mayadas TN. 2008. Role ofEpac1, an exchange factor for Rap GTPases, in endothelial microtubule dynamics and barrier function. Mol. Biol. Cell 19:1261-1270
31. Mei FC, Cheng X. 2005. Interplay between exchange protein directly activated by cAMP (Epac) and microtubule cytoskeleton. Mol. Biosyst. 1:325-331
32. Yarwood SJ. 2005. Microtubule-associated proteins (MAPs) regulate cAMP signaling through exchange protein directly activated by cAMP (EPAC). Biochem. Soc. Trans. 33:1327-1329
33. Brock TG, Serezani CH, CarstensJK, Peters-GoldenM, Aronoff DM. 2008. Effects of prostaglandin E2 on the subcellular localization of Epac-1 and Rap1 proteins during Fcy-receptor-mediated phagocytosis in alveolar macrophages. Exp. Cell Res. 314:255-263
34. WangZ, Dillon TJ, Pokala V, Mishra S, Labudda K, et al. 2006. Rap1-mediated activation of extracellular signal-regulated kinases by cyclic AMP is dependent on the mode of Rap1 activation. Mol. Cell Biol. 26:2130-2145
35. Honegger KJ, Capuano P, Winter C, Bacic D, Stange G, et al. 2006. Regulation of sodium-proton exchanger isoform 3 (NHE3) by PKA and exchange protein directly activated by cAMP (EPAC). Proc. Natl. Acad. Sci. USA 103:803-808
36. Li Y, Konings IB, Zhao J, Price LS, de Heer E, Deen PM. 2008. Renal expression of exchange protein directly activated by cAMP (Epac) 1 and 2. Am. J. Physiol. Renal Physiol. 295:F525-33
37. Lohse MJ, Engelhardt S, Eschenhagen T. 2003. What is the role of |3-adrenergic signaling in heart failure? Circ. Res. 93:896-906
38. Bers DM. 2008. Calcium cycling and signaling in cardiac myocytes. Annu. Rev. Physiol. 70:23-49
39. Wang H, Oestreich EA, Maekawa N, Bullard TA, Vikstrom KL, et al. 2005. Phospholipase Ce modulates |3-adrenergic receptor-dependent cardiac contraction and inhibits cardiac hypertrophy. Circ. Res. 97:1305-1313
40. 2+ mobilization in cardiac myocytes. J. Biol. Chem. 282:5488-5495
41. 2+ release in the heart by activation of protein kinase Ce and calcium-calmodulin kinase II. J. Biol. Chem. 284:1514-1522
42. 2+/calmodulin kinase signaling pathway in rat cardiac myocytes. J. Physiol. 583:685-694
43. Hothi SS, Gurung IS, Heathcote JC, Zhang Y, Booth SW, et al. 2008. Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart. Pflüg. Arch. 457:253-270
44. Morel E, Marcantoni A, Gastineau M, Birkedal R, Rochais F, et al. 2005. cAMP-binding protein Epac induces cardiomyocyte hypertrophy. Circ. Res. 97:1296-1304
45. Somekawa S, Fukuhara S, Nakaoka Y, Fujita H, Saito Y, Mochizuki N. 2005. Enhanced functional gap junction neoformation by protein kinase A\dependent and Epac-dependent signals downstream of cAMP in cardiac myocytes. Circ. Res. 97:655-662
46. Metrich M, Lucas A, Gastineau M, Samuel JL, Heymes C, et al. 2008. Epac mediates |3-adrenergic receptor-induced cardiomyocyte hypertrophy. Circ. Res. 102:959-965
47. Ulucan C, Wang X, Baljinnyam E, Bai Y, Okumura S, et al. 2007. Developmental changes in gene expression of Epac and its upregulation in myocardial hypertrophy. Am. J. Physiol. Heart Circ. Physiol. 293:H1662-72
48. Dodge-Kafka KL, Soughayer J, Pare GC, Carlisle Michel JJ, Langeberg LK, et al. 2005. The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature 437:574-578
49. Kapiloff MS, Jackson N, Airhart N. 2001. mAKAP and the ryanodine receptor are part of a multi-component signaling complex on the cardiomyocyte nuclear envelope. J. Cell Sci. 114:3167-3176
50. Barg S, Lindqvist A, Obermuller S. 2008. Granule docking and cargo release in pancreatic |3-cells. Biochem. Soc. Trans. 36:294-299
51. Doyle ME, Egan JM. 2007. Mechanisms of action of glucagon-like peptide 1 in the pancreas. Pharmacol. Ther. 113:546-593
52. Leech CA, Holz GG, Chepurny O, HabenerJF. 2000. Expression of cAMP-regulated guanine nucleotide exchange factors in pancreatic |3-cells. Biochem. Biophys. Res. Commun. 278:44 47
53. Kashima Y, Miki T, Shibasaki T, Ozaki N, Miyazaki M, et al. 2001. Critical role of cAMP-GEFII-Rim2 complex in incretin-potentiated insulin secretion. J. Biol. Chem. 276:46046-46053
54. 2+ release in INS-1 pancreatic |3-cells. J. Physiol. 536:375-385
55. 2+ release and exocytosis in pancreatic P-cells. J. Biol. Chem. 278:8279-8285
56. 2+ and ATP in rat islet |3-cells. Diabetes Metab. Res. Rev. 22:64-71
57. Kwan EP, Gao X, Leung YM, Gaisano HY 2007
58. Shibasaki T, Takahashi H, Miki T, Sunaga Y, Matsumura K, et al. 2007. Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP. Proc. Natl. Acad. Sci. USA 104:19333-19338
59. 2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 P-cells. Biochem. J. 369:287-299
60. Kang G, Chepurny OG, Malester B, Rindler MJ, Rehmann H, et al. 2006. cAMP sensor Epac as a determinant of ATP-sensitive potassium channel activity in human pancreatic |3 cells and rat INS-1 cells. J. Physiol. 573:595-609
61. Ozaki N, Shibasaki T, Kashima Y, Miki T, Takahashi K, et al. 2000. cAMP-GEFII is a direct target of cAMP in regulated exocytosis. Nat. Cell Biol. 2:805-811
62. 2+ release in mouse pancreatic |3 cells. J. Physiol. 566:173-188
63. 2+ channel in insulin granule exocytosis. J. Biol. Chem. 279:7956-7961
64. 2+ sensor in pancreatic |3-cells. Involvement of cAMP-GEFII. Rim2. Piccolo complexin cAMP-dependent exocytosis. J. Biol. Chem. 277:50497-50502
65. Eliasson L, Ma X, Renstrom E, Barg S, Berggren PO, et al. 2003. SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic |3-cells. J. Gen. Physiol. 121:181-197
66. Zhang CL, Katoh M, Shibasaki T, Minami K, Sunaga Y, et al. 2009. The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs. Science 325:607
67. Sakaba T, Neher E. 2003. Direct modulation of synaptic vesicle priming by GABA(B) receptor activation at a glutamatergic synapse. Nature 424:775-778
68. Cheung U, Atwood HL, Zucker RS. 2006. Presynaptic effectors contributing to cAMP-induced synaptic potentiation in Drosophila. J. Neurobiol. 66:273-280
69. Kaneko M, Takahashi T. 2004. Presynaptic mechanism underlying cAMP-dependent synaptic potentiation. J. Neurosci. 24:5202-5208
70. Gekel I, Neher E. 2008. Application of an Epac activator enhances neurotransmitter release at excitatory central synapses. J. Neurosci. 28:7991-8002
71. 2+-dependent exocytosis through both PKA and Epac2 in mouse melanotrophs from pituitary tissue slices. J. Physiol. 567:799-813
72. 2+, hyperpolarization and cyclic nucleotide-activated channel activation, and actin in temporal synaptic tagging. J. Neurosci. 24:4205-4212
73. Ster J, de Bock F, Bertaso F, Abitbol K, Daniel H, et al. 2009. Epac mediates PACAP-dependent long-term depression in the hippocampus. J. Physiol. 587:101-113
74. Ouyang M, Zhang L, Zhu JJ, Schwede F, Thomas SA 2008. Epac signaling is required for hippocampus-dependent memory retrieval. Proc. Natl. Acad. Sci. USA 105:11993-11997
75. Kelly MP, Stein JM, Vecsey CG, Favilla C, Yang X, et al. 2008. Developmental etiology for neu-roanatomical and cognitive deficits in mice overexpressing Gas, a G protein subunit genetically linked to schizophrenia. Mol. Psychiatry 14:398-415
76. Hucho TB, Dina OA, Kuhn J, Levine JD. 2006. Estrogen controls PKCe-dependent mechanical hyperalgesia through direct action on nociceptive neurons. Eur. J. Neurosci. 24:527-534
77. Hucho TB, Dina OA, Levine JD. 2005. Epac mediates a cAMP-to-PKC signaling in inflammatory pain: anisolectin B4(+) neuron-specific mechanism. J. Neurosci. 25:6119-6126
78. Wang C, Gu Y, Li GW, Huang LY 2007. A critical role of the cAMP sensor Epac in switching protein kinase signaling in prostaglandin E2-induced potentiation of P2 X 3 receptor currents in inflamed rats. J. Physiol. 584:191-203
79. Christensen AE, Selheim F, de Rooij J, Dremier S, Schwede F, et al. 2003. cAMP analog mapping of Epac1 and cAMP kinase. Discriminating analogs demonstrate that Epac and cAMP kinase act synergis-tically to promote PC-12 cell neurite extension. J. Biol. Chem. 278:35394-35402
80. Kiermayer S, Biondi RM, Imig J, Plotz G, Haupenthal J, et al. 2005. Epac activation converts cAMP from a proliferative into a differentiation signal in PC12 cells. Mol. Biol. Cell 16:5639-5648
81. Shi GX, Rehmann H, Andres DA. 2006. A novel cyclic AMP\dependent Epac-Rit signaling pathway contributes to PACAP38-mediated neuronal differentiation. Mol. Cell Biol. 26:9136-9147
82. Lastres-Becker I, Fernandez-Perez A, Cebolla B, Vallejo M. 2008. Pituitary adenylate cyclase-activating polypeptide stimulates glial fibrillary acidic protein gene expression in cortical precursor cells by activating Ras and Rap1. Mol. Cell Neurosci. 39:291-301
83. Murray AJ, Shewan DA. 2008. Epac mediates cyclic AMP-dependent axon growth, guidance and regeneration. Mol. Cell Neurosci. 38:578-588
84. Maillet M, Robert SJ, Cacquevel M, Gastineau M, Vivien D, et al. 2003. Crosstalk between Rap1 and Rac regulates secretion of sAPPα. Nat. Cell Biol. 5:633-639
85. Robert S, Maillet M, Morel E, Launay JM, Fischmeister R, et al. 2005. Regulation of the amyloid precursor protein ectodomain shedding by the 5-HT4 receptor and Epac. FEBS Lett. 579:1136-1142
86. O'Neill JS, Maywood ES, Chesham JE, Takahashi JS, Hastings MH. 2008. cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science 320:949-953
87. Dejana E, Orsenigo F, Lampugnani MG. 2008. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J. Cell Sci. 121:2115-2122
88. Mehta D, Malik AB. 2006. Signaling mechanisms regulating endothelial permeability. Physiol. Rev. 86:279-367
89. Yuan SY. 2002. Protein kinase signalingin the modulation of microvascular permeability. Vasc. Pharmacol. 39:213-223
90. Hogan C, Serpente N, Cogram P, Hosking CR, Bialucha CU, et al. 2004. Rap1 regulates the formation of E-cadherin-based cell-cell contacts. Mol. Cell Biol. 24:6690-6700
91. Price LS, Hajdo-Milasinovic A, Zhao J, Zwartkruis FJ, Collard JG, Bos JL. 2004. Rap1 regulates E-cadherin-mediated cell-cell adhesion. J. Biol. Chem. 279:35127-35132
92. Kooistra MR, Corada M, Dejana E, Bos JL. 2005. Epac1 regulates integrity of endothelial cell junctions through VE-cadherin. FEBS Lett. 579:4966-4972
93. Cullere X, Shaw SK, Andersson L, Hirahashi J, Luscinskas FW, Mayadas TN. 2005. Regulation of vascular endothelial barrier function by Epac, a cAMP-activated exchange factor for Rap GTPase. Blood 105:1950-1955
94. Fukuhara S, Sakurai A, Sano H, Yamagishi A, Somekawa S, et al. 2005. Cyclic AMP potentiates vascular endothelial cadherin-mediated cell-cell contact to enhance endothelial barrier function through an Epac-Rap1 signaling pathway. Mol. Cell Biol. 25:136-146
95. Wittchen ES, Worthylake RA, Kelly P, Casey PJ, Quilliam LA, Burridge K. 2005. Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function. J. Biol. Chem. 280:11675-11682
96. Adamson RH, Ly JC, Sarai RK, Lenz JF, Altangerel A, et al. 2008. Epac/Rap1 pathway regulates mi-crovascular hyperpermeability induced by PAF in rat mesentery. Am. J. Physiol. Heart Circ. Physiol. 294:H1188-96
97. Dudek SM, Garcia JG. 2001. Cytoskeletal regulation of pulmonary vascular permeability. J. Appl. Physiol. 91:1487-1500
98. Birukova AA, Zagranichnaya T, Alekseeva E, Bokoch GM, Birukov KG. 2008. Epac/Rap and PKA are novel mechanisms of ANP-induced Rac-mediated pulmonary endothelial barrier protection. J. Cell Physiol. 215:715-724
99. Birukova AA, Zagranichnaya T, Fu P, Alekseeva E, Chen W, et al. 2007. Prostaglandins PGE(2) and PGI(2) promote endothelial barrier enhancement via PKA-and Epac1/Rap1-dependent Rac activation. Exp. Cell Res. 313:2504-2520
100. Baumer Y, Drenckhahn D, Waschke J. 2008. cAMP induced Rac 1-mediated cytoskeletal reorganization in microvascular endothelium. Histochem. Cell Biol. 129:765-778
101. Dubovsky J, Zabramski JM, Kurth J, Spetzler RF, Rich SS, et al. 1995. A gene responsible for cavernous malformations of the brain maps to chromosome 7q. Hum. Mol. Genet. 4:453-458
102. Hogan BM, Bussmann J, Wolburg H, Schulte-Merker S. 2008. ccm1 cell autonomously regulates en-dothelial cellular morphogenesis and vascular tubulogenesis in zebrafish. Hum. Mol. Genet. 17:2424-2432
103. Whitehead KJ, Chan AC, Navankasattusas S, Koh W, London NR, et al. 2009. The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat. Med. 15:177-184
104. Whitehead KJ, Plummer NW, Adams JA, Marchuk DA, Li DY. 2004. Ccm1 is required for arterial morphogenesis: implications for the etiology of human cavernous malformations. Development 131:1437-1448
105. Kleaveland B, Zheng X, Liu JJ, Blum Y, Tung JJ, et al. 2009. Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway. Nat. Med. 15:169-176
106. Gore AV, Lampugnani MG, Dye L, Dejana E, Weinstein BM. 2008. Combinatorial interaction between CCM pathway genes precipitates hemorrhagic stroke. Dis. Models Mech. 1:275-281
107. Glading A, Han J, Stockton RA, Ginsberg MH. 2007. KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions. J. Cell Biol. 179:247-254
108. Serebriiskii I, Estojak J, Sonoda G, Testa JR, Golemis EA. 1997. Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22. Oncogene 15:1043-1049
109. Birukova AA, Smurova K, Birukov KG, Usatyuk P, Liu F, et al. 2004. Microtubule disassembly induces cytoskeletal remodeling and lung vascular barrier dysfunction: role of Rho-dependent mechanisms. J. Cell Physiol. 201:55-70
110. Sands WA, Woolson HD, Milne GR, Rutherford C, Palmer TM. 2006. Exchange protein activated by cyclic AMP (Epac)-mediated induction of suppressor of cytokine signaling 3 (SOCS-3) in vascular endothelial cells. Mol. Cell Biol. 26:6333-6346
111. Netherton SJ, Sutton JA, Wilson LS, Carter RL, Maurice DH. 2007. Both protein kinase A and exchange protein activated bycAMP coordinate adhesion of human vascular endothelial cells. Circ. Res. 101:768-776
112. Lorenowicz MJ, Fernandez-Borja M, Kooistra MR, Bos JL, Hordijk PL. 2008. PKA and Epac1 regulate endothelial integrity and migration through parallel and independent pathways. Eur. J. Cell Biol. 87:779-792
113. Yokoyama U, Minamisawa S, Quan H, Akaike T, Suzuki S, et al. 2008. Prostaglandin E2-activated Epac promotes neointimal formation of the rat ductus arteriosus by a process distinct from that of cAMP-dependent protein kinase A. J. Biol. Chem. 283:28702-28709
114. Rondaij MG, Sellink E, Gijzen KA, ten Klooster JP, Hordijk PL, et al. 2004. Small GTP-binding protein Ral is involved in cAMP-mediated release of von Willebrand factor from endothelial cells. Arterioscler. Thromb. Vasc. Biol. 24:1315-1320
115. Lorenowicz MJ, van Gils J, de Boer M, Hordijk PL, Fernandez-Borja M. 2006. Epac1-Rap1 signaling regulates monocyte adhesion and chemotaxis. J. Leukoc. Biol. 80:1542-1552
116. Hata AN, Breyer RM. 2004. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol. Ther. 103:147-166
117. Aronoff DM, Canetti C, Serezani CH, Luo M, Peters-Golden M. 2005. Cutting edge: macrophage inhibition by cyclic AMP (cAMP): differential roles of protein kinase A and exchange protein directly activated by cAMP-1. J. Immunol. 174:595-599
118. Canetti C, Serezani CH, Atrasz RG, White ES, Aronoff DM, Peters-Golden M. 2007. Activation of phosphatase and tensin homolog on chromosome 10 mediates the inhibition of FcγR phagocytosis by prostaglandin E2 in alveolar macrophages. J. Immunol. 179:8350-8356
119. Bryn T, Mahic M, Enserink JM, Schwede F, Aandahl EM, Tasken K. 2006. The cyclic AMP-Epac1-Rap1 pathwayis dissociated from regulation of effector functions in monocytes but acquires immunoregulatory function in mature macrophages. J. Immunol. 176:7361-7370
120. Makranz C, Cohen G, Reichert F, Kodama T, Rotshenker S. 2006. cAMP cascade (PKA, Epac, adenylyl cyclase, Gi, and phosphodiesterases) regulates myelin phagocytosis mediated by complement receptor-3 and scavenger receptor-AI/II in microglia and macrophages. Glia 53:441-448
121. Usynin I, Klotz C, Frevert U. 2007. Malaria circumsporozoite protein inhibits the respiratory burst in Kupffer cells. Cell Microbiol. 9:2610-2628
122. Aronoff DM, Carstens JK, Chen GH, Toews GB, Peters-Golden M. 2006. Short communication: differences between macrophages and dendritic cells in the cyclic AMP-dependent regulation of lipopolysaccharide-induced cytokine and chemokine synthesis. J. Interferon Cytokine Res. 26:827-833
123. Jing H, Yen JH, Ganea D. 2004. A novel signaling pathway mediates the inhibition of CCL3/4 expression by prostaglandin E2. J. Biol. Chem. 279:55176-55186
124. Tan KS, Nackley AG, Satterfield K, Maixner W, Diatchenko L, Flood PM. 2007. β2 adrenergic receptor activation stimulates proinflammatory cytokine production in macrophages via PKA-and NF-κB-independent mechanisms. Cell Signal. 19:251-260
125. Xu XJ, Reichner JS, Mastrofrancesco B, Henry WL Jr., Albina JE. 2008. Prostaglandin E2 suppresses lipopolysaccharide-stimulated IFN-β production. J. Immunol. 180:2125-2131
126. Scheibner KA, Boodoo S, Collins S, Black KE, Chan-Li Y, et al. 2009. The adenosine a2a receptor inhibits matrix-induced inflammation in a novel fashion. Am. J. Respir. Cell Mol. Biol. 40:251-259
127. Bos JL. 2005. Linking Rap to cell adhesion. Curr. Opin. Cell Biol. 17:123-128
128. Shimonaka M, Katagiri K, Nakayama T, Fujita N, Tsuruo T, et al. 2003. Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow. J. Cell Biol. 161:417-427
129. Gerard A, Mertens AE, Van Der Kammen RA, Collard JG. 2007. The Par polarity complex regulates Rap1-and chemokine-induced T cell polarization. J. Cell Biol. 176:863-875
130. Laroche-Joubert N, Marsy S, Michelet S, Imbert-Teboul M, Doucet A. 2002. Protein kinase A-independent activation of ERK and H, K-ATPase by cAMP in native kidney cells: role of Epac I. J. Biol. Chem. 277:18598-18604
131. (+) exchanger regulatory factor 1 (NHERF1) null mice. cAMP inhibition is differentially dependent on NHERF1 and exchange protein directly activated by cAMP in ileum versus proximal tubule. J. Biol. Chem. 282:25141-25151
132. (+) exchanger 3 (NHE3) activity in NHE regulatory factor 1 (NHERF1) adaptor protein-deficient mice. Pflüg. Arch. 457:1079-1091
133. 2+ mobilization and exocytosis in inner medullary collecting duct. Am. J. Physiol. Renal Physiol. 291:F882-90
134. Helms MN, Chen XJ, Ramosevac S, Eaton DC, Jain L. 2006. Dopamine regulationofamiloride-sensitive sodium channels in lung cells. Am. J. Physiol. Lung Cell Mol. Physiol. 290:L710-22
135. - channels in rat hepatocytes. J. Physiol. 573:611-625
136. Lopez De Jesus M, Stope MB, Oude Weernink PA, Mahlke Y, Borgermann C, et al. 2006. Cyclic AMP-dependent and Epac-mediated activationofR-RasbyGprotein- coupled receptors leadsto phospholipase D stimulation. J. Biol. Chem. 281:21837-21847
137. Rehmann H, Prakash B, Wolf E, Rueppel A, de Rooij J, et al. 2003. Structure and regulation of the cAMP-binding domains of Epac2. Nat. Struct. Biol. 10:26-32
138. McPhee I, Gibson LC, Kewney J, Darroch C, Stevens PA, et al. 2005. Cyclic nucleotide signaling: a molecular approach to drug discovery for Alzheimer's disease. Biochem. Soc. Trans. 33:1330-1332
139. Carmona G, Chavakis E, Koehl U, Zeiher AM, Dimmeler S. 2008. Activation of Epac stimulates integrin-dependent homing of progenitor cells. Blood 111:2640-2646