Crosstalk between Rap1 and Rac regulates secretion of sAPPalpha.
Cyclic AMP (cAMP) is produced by activation of Gs protein-coupled receptors and regulates many physiological processes through activation of protein kinase A (PKA). However, a large body of evidence indicates that cAMP also regulates specific cellular functions through PKA-independent pathways. Here, we show that a small GTPase of the Rho family, Rac, is regulated by cAMP in a PKA-independent manner. We also show that Rac activation results from activation of Rap1 through the cAMP guanine nucleotide-exchange factor (GEF) Epac1. Activation of the Gs-coupled serotonin 5-HT(4) receptor initiates this signalling cascade in various cell types. Furthermore, we demonstrate that crosstalk between the Ras and Rho GTPase families is involved in cAMP-dependent processing of amyloid precursor protein (APP), a key protein in Alzheimer's disease. Indeed, Epac1 regulates secretion of the non-amyloidogenic soluble form of APP (sAPPalpha) through Rap1 and Rac. Our data identify an unsuspected connection between two families of small GTPases and imply that Rac can function downstream of cAMP/Epac1/Rap1 in a novel signal transduction secretory pathway.
Maillet
Marjorie
M
Cardiologie Cellulaire et Moléculaire, INSERM U-446, Université Paris-Sud, Faculté de Pharmacie, F-92296 Châtenay-Malabry, France.
Robert
Sylvain J
SJ
Cacquevel
Mathias
M
Gastineau
Monique
M
Vivien
Denis
D
Bertoglio
Jacques
J
Zugaza
José L
JL
Fischmeister
Rodolphe
R
Lezoualc'h
Frank
F
D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002540:Cerebral Cortex / Q000201:enzymology* / Q000503:physiopathology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000201:enzymology*; D011985:Receptors, Serotonin / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4; D015398:Signal Transduction / Q000235:genetics; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D011985:Receptors, Serotonin; D044422:Receptors, Serotonin, 5-HT4; D000242:Cyclic AMP; D020744:rac GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins