EGR1 and the ERK‐ERF axis drive mammary cell migration in response to EGF

• Published in: The FASEB journal Vol. 26; no. 4; pp. 1582 - 1592
• Main Authors: Tarcic, Gabi, Avraham, Roi, Pines, Gur, Amit, Ido, Shay, Tal, Lu, Yiling, Zwang, Yaara, Katz, Menachem, Ben‐Chetrit, Nir, Jacob‐Hirsch, Jasmine, Virgilio, Laura, Rechavi, Gideon, Mavrothalassitis, George, Mills, Gordon B., Domany, Eytan, Yarden, Yosef
• Format: Journal Article
• Language: English
• Published: Bethesda, MD, USA Federation of American Societies for Experimental Biology 01-04-2012
• Subjects: Cell Line; Cell Movement - drug effects; Cell Proliferation - drug effects; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; Epidermal Growth Factor - pharmacology; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gene Expression Profiling; growth factor; Humans; Mammary Glands, Human - cytology; Microarray Analysis; MicroRNAs - genetics; MicroRNAs - metabolism; negative feedback; phosphorylation; Proteome - analysis; Repressor Proteins - genetics; Repressor Proteins - metabolism; Research Communications; Signal Transduction - drug effects; Signal Transduction - physiology; transcription; Two-Hybrid System Techniques
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.11-194654

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