Extracellular signal-regulated protein kinase 5 (ERK5) is a mitogen-activated protein kinase, specifically activated by MEK5, and involved in the regulation of many cellular functions including proliferation, survival, differentiation and apoptosis. MEK5/ERK5 module is an important element of different signal transduction pathways. The aim of this study was to investigate whether ERK5 participates to the signalling of the multifunctional cytokine TGFbeta, known to play an important role in the regulation of hepatic growth. Here, we reported that ERK5 is phosphorylated and activated by TGFbeta in hepatocytes, with a rapid and sustained kinetic, through a Src-dependent pathway. Moreover, we demonstrated that ERK5 participates to the TGFbeta-induced Snail protein regulation being required for its stabilization. We also found that the functional inactivation of ERK5 impedes the TGFbeta-mediated glycogen synthase kinase-3beta inactivation suggesting this as mechanism responsible for ERK5-mediated Snail stabilization. Thus, results presented in this study uncovered for the first time a role for ERK5 in the TGFbeta-induced cellular responses.