Epac: effectors and biological functions.

Sara S Roscioni, Carolina R S Elzinga, Martina Schmidt
Author Information
  1. Sara S Roscioni: Department of Molecular Pharmacology, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.

Abstract

Epac1 (also known as cAMP-GEF-I) and Epac2 (also known as cAMP-GEF-II) are cyclic AMP-activated guanine nucleotide exchange factors for Ras-like GTPases. Since their discovery about 10 years ago, it is now accepted that Epac proteins are novel cAMP sensors that regulate several pivotal cellular processes, including calcium handling, cell proliferation, cell survival, cell differentiation, cell polarization, cell-cell adhesion events, gene transcription, secretion, ion transport, and neuronal signaling. Recent studies even indicated that Epac proteins might play a role in the regulation of inflammation and the development of cardiac hypertrophy. Meanwhile, a plethora of diverse effectors of Epac proteins have been assigned, such as Ras and Rho GTPases, phospholiase C-epsilon, phospholipase D, mitogen-activated protein kinases, protein kinase B/Akt, ion channels, secretory-granule associated proteins and regulators of the actin-microtubule network, the latter probably involved in the spatiotemporal dynamics of Epac-related signaling. This review highlights multi-faceted effectors and diverse biological functions driven by Epac proteins that might explain certain controversial signaling properties of cAMP.

References

Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):803-8 [PMID: 16407144]
J Biol Chem. 2004 Jul 9;279(28):29121-9 [PMID: 15128746]
Nat Rev Drug Discov. 2007 Jul;6(7):541-55 [PMID: 17585331]
Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1662-72 [PMID: 17557924]
Science. 2004 Feb 6;303(5659):839-42 [PMID: 14764880]
J Biol Chem. 2002 May 24;277(21):18598-604 [PMID: 11897793]
J Physiol. 2007 Nov 1;584(Pt 3):1029-31 [PMID: 17884917]
J Physiol. 2006 Jun 15;573(Pt 3):595-609 [PMID: 16613879]
J Biol Chem. 2000 Jul 7;275(27):20829-36 [PMID: 10777494]
Nat Rev Mol Cell Biol. 2003 Oct;4(10):767-76 [PMID: 14570053]
J Biol Chem. 2005 Nov 18;280(46):38276-89 [PMID: 16172130]
J Neurosci. 2002 Mar 15;22(6):2106-14 [PMID: 11896150]
J Biol Chem. 2004 Nov 19;279(47):49488-96 [PMID: 15342639]
J Leukoc Biol. 2006 Dec;80(6):1542-52 [PMID: 16940330]
J Cell Sci. 2003 Feb 1;116(Pt 3):435-40 [PMID: 12508104]
Mol Cell Biol. 2006 Sep;26(17 ):6333-46 [PMID: 16914720]
FEBS Lett. 2005 Sep 12;579(22):4966-72 [PMID: 16115630]
EMBO J. 2001 Feb 15;20(4):743-54 [PMID: 11179219]
J Cell Sci. 2001 Jun;114(Pt 11):2145-54 [PMID: 11493650]
Trends Cell Biol. 2004 Jul;14(7):377-85 [PMID: 15246431]
J Cell Sci. 2007 Jan 1;120(Pt 1):17-22 [PMID: 17182900]
EMBO Rep. 2004 Dec;5(12):1176-80 [PMID: 15550931]
J Cell Sci. 2001 Apr;114(Pt 7):1357-66 [PMID: 11257001]
Nature. 2006 May 25;441(7092):424-30 [PMID: 16724053]
J Biol Chem. 2006 Aug 4;281(31):21837-47 [PMID: 16754664]
Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2519-24 [PMID: 17284589]
Curr Biol. 2005 Jul 26;15(14):R563-74 [PMID: 16051167]
Trends Cell Biol. 2002 Jun;12(6):258-66 [PMID: 12074885]
Nat Rev Mol Cell Biol. 2002 Dec;3(12 ):957-64 [PMID: 12461561]
Mol Pharmacol. 2001 Nov;60(5):924-33 [PMID: 11641420]
J Biol Chem. 2007 Feb 23;282(8):5488-95 [PMID: 17178726]
Nat Rev Mol Cell Biol. 2005 Feb;6(2):167-80 [PMID: 15688002]
Nat Rev Mol Cell Biol. 2001 May;2(5):369-77 [PMID: 11331911]
Nat Rev Mol Cell Biol. 2004 Dec;5(12):959-70 [PMID: 15573134]
Cell Signal. 2004 Aug;16(8):921-8 [PMID: 15157671]
Curr Opin Cell Biol. 2005 Apr;17(2):123-8 [PMID: 15780587]
J Biol Chem. 2006 May 19;281(20):14026-40 [PMID: 16565089]
Nat Rev Mol Cell Biol. 2007 Mar;8(3):221-33 [PMID: 17318226]
J Immunol. 2006 Jun 15;176(12):7361-70 [PMID: 16751380]
J Biol Chem. 2002 Jun 7;277(23):20160-8 [PMID: 11914372]
J Biol Chem. 2003 Sep 12;278(37):35394-402 [PMID: 12819211]
J Biol Chem. 2001 Aug 10;276(32):30301-7 [PMID: 11395506]
Curr Opin Cell Biol. 2005 Apr;17(2):150-7 [PMID: 15780591]
Mol Cell Biol. 1999 Sep;19(9):5882-91 [PMID: 10454535]
Mol Pharmacol. 2006 Jan;69(1):374-84 [PMID: 16244178]
Biochim Biophys Acta. 2005 Dec 30;1746(3):274-83 [PMID: 16039730]
J Biol Chem. 2006 Jul 28;281(30):21500-11 [PMID: 16728394]
Exp Cell Res. 2007 Jul 1;313(11):2504-20 [PMID: 17493609]
Mol Biosyst. 2005 Oct;1(4):325-31 [PMID: 16880999]
J Neurosci. 2005 Jan 5;25(1):208-14 [PMID: 15634783]
Cell Signal. 2008 Jan;20(1):10-20 [PMID: 17716863]
J Biol Chem. 2002 Mar 29;277(13):11497-504 [PMID: 11801596]
J Cell Sci. 2005 Mar 1;118(Pt 5):843-6 [PMID: 15731001]
Curr Opin Cell Biol. 2006 Aug;18(4):351-7 [PMID: 16781855]
Biochem J. 2004 Sep 15;382(Pt 3):803-10 [PMID: 15202935]
Cell Signal. 2007 Jan;19(1):81-6 [PMID: 16839743]
Circ Res. 2005 Sep 30;97(7):655-62 [PMID: 16123333]
Nature. 2005 Sep 22;437(7058):574-8 [PMID: 16177794]
J Physiol. 2007 Sep 1;583(Pt 2):685-94 [PMID: 17599964]
EMBO J. 2005 Mar 9;24(5):985-96 [PMID: 15706349]
Nat Cell Biol. 2003 Jul;5(7):633-9 [PMID: 12819788]
Am J Physiol Renal Physiol. 2006 Oct;291(4):F882-90 [PMID: 16684923]
Trends Cardiovasc Med. 2004 Apr;14(3):100-5 [PMID: 15121157]
J Biol Chem. 2002 Jul 19;277(29):26581-6 [PMID: 12000763]
Nature. 2006 Feb 2;439(7076):625-8 [PMID: 16452984]
Blood. 2004 Apr 1;103(7):2661-7 [PMID: 14615375]
Nat Cell Biol. 2002 Apr;4(4):294-301 [PMID: 11912491]
Cell Mol Life Sci. 2002 May;59(5):761-79 [PMID: 12088277]
Endocrinology. 2006 Aug;147(8):3727-36 [PMID: 16644915]
Curr Opin Pharmacol. 2007 Apr;7(2):193-200 [PMID: 17276729]
Mol Cell Biol. 2006 Dec;26(23):9136-47 [PMID: 17000774]
Mol Cell Biol. 2006 Mar;26(6):2130-45 [PMID: 16507992]
Nature. 1997 Aug 7;388(6642):593-8 [PMID: 9252191]
Cell. 2007 Jun 1;129(5):865-77 [PMID: 17540168]
Diabetes. 2003 Mar;52(3):767-76 [PMID: 12606519]
Biochem J. 1998 May 15;332 ( Pt 1):173-81 [PMID: 9576865]
J Biol Chem. 2001 Jan 26;276(4):2758-65 [PMID: 11022047]
J Pharmacol Exp Ther. 2007 Sep;322(3):1189-200 [PMID: 17565009]
Nat Rev Mol Cell Biol. 2003 Jul;4(7):517-29 [PMID: 12838335]
Nat Cell Biol. 2001 Nov;3(11):1020-4 [PMID: 11715024]
J Mol Biol. 2000 Jun 9;299(3):551-72 [PMID: 10835267]
Science. 2001 Nov 30;294(5548):1942-5 [PMID: 11729323]
Nat Cell Biol. 2000 Nov;2(11):805-11 [PMID: 11056535]
EMBO J. 2003 Feb 17;22(4):859-69 [PMID: 12574122]
Science. 1998 Dec 18;282(5397):2275-9 [PMID: 9856955]
Nature. 1998 Dec 3;396(6710):474-7 [PMID: 9853756]
Physiol Rev. 2005 Oct;85(4):1303-42 [PMID: 16183914]
Cell Signal. 2005 Dec;17(12):1551-9 [PMID: 15908181]
J Biol Chem. 2004 Apr 16;279(16):15711-4 [PMID: 14966141]
Nat Rev Mol Cell Biol. 2004 Aug;5(8):601-13 [PMID: 15366704]
Regul Pept. 2006 Nov 15;137(1-2):50-7 [PMID: 17011642]
Curr Biol. 2004 Aug 10;14(15):1380-4 [PMID: 15296756]
J Biol Chem. 2004 Mar 5;279(10 ):8938-45 [PMID: 14688288]
J Biol Chem. 2001 Jul 27;276(30):28478-83 [PMID: 11359771]
J Biol Chem. 2001 Jan 26;276(4):2752-7 [PMID: 11022048]
J Biol Chem. 2004 Nov 5;279(45):46497-508 [PMID: 15319437]
J Physiol. 2006 Jun 15;573(Pt 3):611-25 [PMID: 16581855]
Prog Nucleic Acid Res Mol Biol. 2002;71:391-444 [PMID: 12102558]
Science. 1998 Nov 6;282(5391):1141-4 [PMID: 9804555]
Trends Mol Med. 2006 Jul;12(7):317-23 [PMID: 16809066]
Blood. 2005 Mar 1;105(5):1950-5 [PMID: 15374886]
Drug Discov Today. 2007 Feb;12(3-4):112-24 [PMID: 17275731]
J Biol Chem. 2003 Sep 5;278(36):33738-46 [PMID: 12783872]
J Biol Chem. 2004 Sep 3;279(36):37215-8 [PMID: 15231839]
Cancer Res. 2007 Jan 1;67(1):1-4 [PMID: 17210675]
Trends Biochem Sci. 2006 Dec;31(12):680-6 [PMID: 17084085]
J Cell Biol. 2003 Feb 17;160(4):487-93 [PMID: 12578910]
Rev Physiol Biochem Pharmacol. 2002;144:1-94 [PMID: 11987824]
Biochem Soc Trans. 2003 Feb;31(Pt 1):83-6 [PMID: 12546659]
Nat Rev Mol Cell Biol. 2002 Sep;3(9):710-8 [PMID: 12209131]
J Biol Chem. 2002 May 10;277(19):16805-13 [PMID: 11877431]
Biochem Soc Trans. 2005 Dec;33(Pt 6):1327-9 [PMID: 16246110]
J Biol Chem. 2006 Feb 3;281(5):2506-14 [PMID: 16316996]
Trends Biochem Sci. 2003 May;28(5):267-75 [PMID: 12765839]
Nat Rev Mol Cell Biol. 2002 May;3(5):339-48 [PMID: 11988768]
Mol Endocrinol. 2000 Aug;14 (8):1283-300 [PMID: 10935551]
Nat Cell Biol. 2002 Mar;4(3):232-9 [PMID: 11862216]
Trends Cell Biol. 2006 Dec;16(12):640-8 [PMID: 17085049]
Oncogene. 2005 Jan 6;24(1):90-100 [PMID: 15558028]
J Cell Sci. 2001 Apr;114(Pt 8):1431-7 [PMID: 11282019]
J Biol Chem. 2003 Mar 7;278(10):8279-85 [PMID: 12496249]
Physiol Rev. 2001 Jan;81(1):153-208 [PMID: 11152757]
Endocr Rev. 2001 Apr;22(2):153-83 [PMID: 11294822]
J Cell Sci. 2006 Apr 1;119(Pt 7):1307-19 [PMID: 16537651]
J Biol Chem. 2005 Mar 4;280(9):8109-16 [PMID: 15591041]
Annu Rev Pharmacol Toxicol. 1996;36:659-701 [PMID: 8725405]
FEBS Lett. 2005 Feb 14;579(5):1136-42 [PMID: 15710402]
Annu Rev Cell Dev Biol. 2005;21:247-69 [PMID: 16212495]
J Biol Chem. 2003 Apr 18;278(16):13672-9 [PMID: 12586830]
Nat Cell Biol. 2002 Nov;4(11):901-6 [PMID: 12402047]
J Physiol. 2006 Nov 15;577(Pt 1):5-15 [PMID: 16973695]
Circ Res. 2005 Dec 9;97(12):1296-304 [PMID: 16269655]
J Biol Chem. 2004 Aug 20;279(34):35127-32 [PMID: 15166221]
Growth Factors. 2005 Jun;23(2):143-9 [PMID: 16019436]
Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16513-8 [PMID: 15545605]
Nat Rev Mol Cell Biol. 2003 Sep;4(9):733-8 [PMID: 14506476]
J Neurochem. 2003 Dec;87(5):1076-85 [PMID: 14622088]
J Biol Chem. 2001 Dec 7;276(49):46046-53 [PMID: 11598134]

MeSH Term

Animals
Calcium Signaling
Cell Physiological Phenomena
Cyclic AMP
Exocytosis
Guanine Nucleotide Exchange Factors
Humans
Ion Channels
Microtubules
Signal Transduction

Chemicals

Guanine Nucleotide Exchange Factors
Ion Channels
RAPGEF3 protein, human
RAPGEF4 protein, human
Cyclic AMP

Word Cloud

Similar Articles

Cited By