beta1 integrins modulate p66ShcA expression and EGF-induced MAP kinase activation in fetal lung cells.
ShcA proteins mediate Erk1/Erk2 activation by integrins and epidermal growth factor (EGF), and are expressed as p46ShcA, p52ShcA, and p66ShcA. Although p52ShcA and p46ShcA mediate Erk1/Erk2 activation, p66ShcA antagonizes Erk activation. p66ShcA is spatially regulated during lung development, leading us to hypothesize that integrin signaling regulates p66ShcA 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. p66ShcA expression was decreased by anti-alpha1 integrin antibody and DGEA collagen analog, and increased by anti-beta1, anti-alpha4, and anti-alpha5 integrin antibodies and RGDS fibronectin analog. Paradoxically, beta1 integrin stimulation increased EGF-induced Erk activation while increasing expression of the inhibitory p66ShcA isoform. This paradox was resolved by demonstrating that Erk inhibition attenuates integrin-mediated p66ShcA induction. These results suggest that p66ShcA is up-regulated as inhibitory feedback on integrin-mediated Erk activation.
Smith
Susan M
SM
Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, Los Angeles, CA, USA.
Crowe
David L
DL
Lee
Matt K
MK
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D018929:Cell Culture Techniques; D002469:Cell Separation; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005333:Fetus / Q000166:cytology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D019012:Integrin beta1 / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000166:cytology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009842:Oligopeptides / Q000819:agonists; D020033:Protein Isoforms / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D015854:Up-Regulation / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D019012:Integrin beta1; D009842:Oligopeptides; D020033:Protein Isoforms; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1