The early gene early growth response (Egr‐1), a broadly expressed member of the zing‐finger family of transcription factors, is induced in many cell types by a variety of growth and differentiation stimuli, including epidermal growth factor (EGF). Here we demonstrate that Egr‐1 expression is mainly regulated by integrin‐mediated adhesion. Integrin‐dependent adhesion plays a dual role in Egr‐1 regulation, either being sufficient “per se” to induce Egr‐1, or required for EGF‐dependent expression of Egr‐1, which occurs only in adherent cells and not in cells in suspension. To dissect the molecular basis of integrin‐dependent Egr‐1 regulation, we show by FLIM‐based FRET that in living cells beta1‐integrin associates with the EGF receptor (EGFR) and that EGF further increases the extent complex formation. Interestingly, Egr‐1 induction depends on integrin‐dependent PI3K/Akt activation, as indicated by the decrease in Egr‐1 levels in presence of the pharmacological inhibitor LY294002, the kinase‐defective Akt mutant and Akt1/2 shRNAs. Indeed, upon adhesion activated Akt translocates into the nucleus and phosphorylates FoxO1, a Forkhead transcription factors. Consistently, FoxO1silencing results in Egr‐1‐increased levels, indicating that FoxO1 behaves as a negative regulator of Egr‐1 expression. These data demonstrate that integrin/EGFR cross‐talk is required for expression of Egr‐1 through a novel regulatory cascade involving the activation of the PI3K/Akt/Forkhead pathway. J. Cell. Physiol. 218: 294–303, 2009. © 2008 Wiley‐Liss, Inc.