Letter abstract
Nature Cell Biology 5, 633 - 639 (2003)
Published online: 22 June 2003 | doi:10.1038/ncb1007
Crosstalk between Rap1 and Rac regulates secretion of sAPP
Marjorie Maillet1,4, Sylvain J. Robert1,3,4, Mathias Cacquevel5, Monique Gastineau1,4, Denis Vivien5, Jacques Bertoglio2,4, José L. Zugaza2,4,6,6, Rodolphe Fischmeister1,4 & Frank Lezoualc'h1,4
Cyclic AMP (cAMP) is produced by activation of Gs protein-coupled receptors and regulates many physiological processes through activation of protein kinase A (PKA)1, 2. However, a large body of evidence indicates that cAMP also regulates specific cellular functions through PKA-independent pathways3, 4. 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-HT4 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 (sAPP
) 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.
- Cardiologie Cellulaire et Moléculaire, INSERM U-446, Université Paris-Sud, Faculté de Pharmacie, F-92296 Châtenay-Malabry, France.
- Récepteurs et Signalisation des Interleukines, INSERM U-461, Université Paris-Sud, Faculté de Pharmacie, F-92296 Châtenay-Malabry, France.
- Neuropharmacologie, EA2707, Université Paris-Sud, Faculté de Pharmacie, F-92296 Châtenay-Malabry, France.
- Institut de Signalisation et Innovation Thérapeutique (IFR 75) Université Paris-Sud, Faculté de Pharmacie, F-92296 Châtenay-Malabry, France.
- UMR CNRS 6551, Centre Cyceron, IFR 47, 14074 Caen Cedex, France.
- Present address: Centro de Investigación del Cáncer, Campus Miguel de Unamuno 37007 Salamanca, Spain.
Correspondence to: José L. Zugaza2,4,6,6 e-mail: jzugaza@usal.es
Correspondence to: Frank Lezoualc'h1,4 e-mail: Frank.Lezoualch@cep.u-psud.fr
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