Autophagy plays an important role in cellular remodelling during differentiation and development, however little is known about its regulation in stem cells. Here we show that cAMP, a well-known differentiation factor for mesenchymal stem cells (MSCs), is also a potent inducer of autophagy in these cells. We have previously shown that activation of the cAMP-signaling pathway inhibits proliferation of MSCs despite induction of the cell cycle component cyclin E. Here, we demonstrate a critical role of cyclin E in the induction of autophagy. Our data suggest a model in which cAMP-signaling via ERK-mediated induction of cyclin E leads to enhanced perinuclear recruitment of Beclin 1 and formation of autophagosomes. Given the roles of deregulated autophagy in neurodegenerative disorders and cAMP as a neurogenic inducer, identification of this novel autophagocytic pathway may provide new targets for intervention against neurological disorders.