title: EGR1 and the ERK-ERF axis drive mammary cell migration in response to EGF.
abstract: 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.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Gabi
authors.initials: G
authors.lastname: Tarcic
authors.forename: Roi
authors.initials: R
authors.lastname: Avraham
authors.forename: Gur
authors.initials: G
authors.lastname: Pines
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
authors.forename: Tal
authors.initials: T
authors.lastname: Shay
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.forename: Yaara
authors.initials: Y
authors.lastname: Zwang
authors.forename: Menachem
authors.initials: M
authors.lastname: Katz
authors.forename: Nir
authors.initials: N
authors.lastname: Ben-Chetrit
authors.forename: Jasmine
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: Laura
authors.initials: L
authors.lastname: Virgilio
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: George
authors.initials: G
authors.lastname: Mavrothalassitis
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Eytan
authors.initials: E
authors.lastname: Domany
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
mesh_terms: D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D046228:Microarray Analysis; D020543:Proteome / Q000032:analysis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D020798:Two-Hybrid System Techniques
chemical_list: C497325:EGR1 protein, human; C107465:ERF protein, human; D051766:Early Growth Response Protein 1; C546177:MIRN191 microRNA, human; D035683:MicroRNAs; D020543:Proteome; D012097:Repressor Proteins; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases