Background and aims: Recent findings suggest that growth factor receptor-mediated motility is one of the most common aberrations of tumour cells that render them invasive.The epidermal growth factor (EGF) signaling pathway is critically involved in cancer metastasis and is known to enhance cell motiliy in a variety of tumour cells.Furthermore, insulin receptor substrates (IRSs) have been recently involved as key proteins for controlling cell migration and invasive processes in response to growth factors, such as EGF.Recently, it has been described a modulating role of AKT and ERK pathways in HepG2 cells migration and adhesion.We have studied the role of IRS-4 in HepG2 cells motility stimulated by EGF as well as the mechanism involved Methods.IRS-4 expression was silenced through siRNA.Proteins regulated by IRS-4 in EGF pathway were analysed by Western blotting and immunoprecipitation.After IRS-4 silencing, changes in cell morphology and invasive capacity induced by EGF were analized by confocal microscopy and cell migration assay (Carloni et al, Gastroenterology 1998), respectively.Results and conclusions: Our results show that in HepG2 cells IRS-4 specific depletion stimulates cell motility through FAK/AKT cascade activation.MEK/ERK and AKT cascades are important in HepG2 cells motility since we have observed that PD098059 (MEK inhibitor) and Ly294002 (PI3K inhibitor) inhibit completely EGF effect on cell invasiveness.When IRS-4 expression was silenced through siRNA, basal values of FAK and AKT decreased.This effect on basal activity had an impact in FAK/AKT cascade stimulation by EGF.Collectively, our data suggest that IRS-4 down regulation stimulated AKT basal activity rendering the HepG2 cells were sensitive to EGF.If confirmed IRS-4 could be a potential target for hepatocellular carcinoma treatment.