ShcA proteins mediate Erk1/Erk2 activation by integrins and epidermal growth factor (EGF), and are expressed as p46(ShcA), p52(ShcA), and p66(ShcA). Although p52(ShcA) and p46(ShcA) mediate Erk1/Erk2 activation, p66(ShcA) antagonizes Erk activation. p66(ShcA) is spatially regulated during lung development, leading us to hypothesize that integrin signaling regulates p66(ShcA) expression and, consequently, EGF signaling. Fetal lung mesenchymal cells were isolated from E16 Swiss-Webster mice, stimulated with oligopeptide extracellular matrix analogs or anti-integrin antibodies, and subjected to ShcA Western analyses and EGF-stimulated Erk1/Erk2 kinase assays. p66(ShcA) expression was decreased by anti-alpha(1) integrin antibody and DGEA collagen analog, and increased by anti-beta(1), anti-alpha(4), and anti-alpha(5) integrin antibodies and RGDS fibronectin analog. Paradoxically, beta(1) integrin stimulation increased EGF-induced Erk activation while increasing expression of the inhibitory p66(ShcA) isoform. This paradox was resolved by demonstrating that Erk inhibition attenuates integrin-mediated p66(ShcA) induction. These results suggest that p66(ShcA) is up-regulated as inhibitory feedback on integrin-mediated Erk activation. (c) 2006 Elsevier Inc. All rights reserved.