Journal
FASEB JOURNAL
Volume 26, Issue 4, Pages 1582-1592Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.11-194654
Keywords
growth factor; phosphorylation; transcription; negative feedback
Categories
Funding
- U.S. National Cancer Institute [CA072981, CA121994-01, CA120248-01]
- European Commission
- German-Israeli Project Cooperation
- Israel Cancer Research Fund
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Kekst Family Institute for Medical Genetics
- Kirk Center for Childhood Cancer and Immunological Disorders
- Women's Health Research Center
- Bennett-Pritzker Endowment Fund
- Marvelle Koffler Program for Breast Cancer Research
- Leir Charitable Foundation
- M. D. Moross Institute for Cancer Research
- Susan G. Komen Foundation
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The signaling pathways that commit cells to migration are incompletely understood. We employed human mammary cells and two stimuli: epidermal growth factor (EGF), which induced cellular migration, and serum factors, which stimulated cell growth. In addition to strong activation of ERK by EGF, and AKT by serum, early transcription remarkably differed: while EGF induced early growth response-1 (EGR1), and this was required for migration, serum induced c-Fos and FosB to enhance proliferation. We demonstrate that induction of EGR1 involves ERK-mediated down-regulation of microRNA-191 and phosphorylation of the ETS2 repressor factor (ERF) repressor, which subsequently leaves the nucleus. Unexpectedly, knockdown of ERF inhibited migration, which implies migratory roles for exported ERF molecules. On the other hand, chromatin immunoprecipitation identified a subset of direct EGR1 targets, including EGR1 autostimulation and SERPINB2, whose transcription is essential for EGF-induced cell migration. In summary, EGR1 and the EGF-ERK-ERF axis emerge from our study as major drivers of growth factor-induced mammary cell migration.-Tarcic, G., Avraham, R., Pines, G., Amit, I., Shay, T., Lu, Y., Zwang, Y., Katz, M., Ben-Chetrit, N., Jacob-Hirsch, J., Virgilio, L., Rechavi, G., Mavrothalassitis, G., Mills, G. B., Domany, E., Yarden, Y. EGR1 and the ERK-ERF axis drive mammary cell migration in response to EGF. FASEB J. 26, 1582-1592 (2012). www.fasebj.org
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