Epac (Exchange protein directly activated by cAMP), a guanine exchange factor (GEF) for the Ras-like GTPases Rap, has been identified as a novel cAMP sensor, alongside of PKA. We have previously shown that Epac activation, through β-adrenergic receptor stimulation, induces cardiomyocyte hypertrophy (Morel et al, 2005, Metrich et al, 2008).This work was intended to identify the component of the Epac signaling cascade leading to cardiac hypertrophy and in particular the implication of the Epac—induced small G proteins and theirs networks.In cardiomyocyte primary culture, we show that Epac activates the small G protein Ras, Rac and Rap. The Epac-induced hypertrophic effect is mediated by Ras and Rac activation. This Epac-induced activation of Ras is not influenced by Rac or Rap and is due to a Ca2+ release in response to phospholipase C and IP3 receptor activation. Moreover, we show that Ras mediates the Epac-induced activation of the pro-hypertrophic CaMKII/MEF2 and calcineurin/ NFAT signalling pathways which are both necessary for hypertrophy. Epac has been initially identified as a GEF for the small G proteins Rap. Surprisingly, the Epac hypertrophic effect is independent of its classical effector Rap. The Epac-induced Rap1 signalling cascade involves PKCɛ translocation, which is a key actor of multiple cellular phosphorylations. This finding is in agreement with other Rap functions reported in the literature such as cell to cell communication and adhesion.Altogether, these data present new insights into the Epac signaling network with both pro-hypertrophic and non-hypertrophic effects.-Morel E, Marcantoni A, Gastineau M, Birkedal R, Rochais F, Garnier A, Lompré AM, Vandecasteele G, Lezoualc’h F. cAMP-binding protein Epac induces cardiomyocyte hypertrophy. Circ Res. 97 : 1296-304, 2005-Métrich M, Lucas A, Gastineau M, Samuel JL, Heymes C, Morel E, Lezoualc’h F.Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy. Circ Res. 102 : 959-65, 2008