title: RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cells.
abstract: The RAS-stimulated RAF-MEK-ERK pathway confers epithelial cells with critical motile and invasive capacities during development, tissue regeneration, and carcinoma progression, often via promoting the epithelial-mesenchymal transition (EMT). Many mechanisms by which ERK exerts this control remain elusive. We demonstrate that the ERK-activated kinase RSK is necessary to induce mesenchymal motility and invasive capacities in nontransformed epithelial and carcinoma cells. RSK is sufficient to induce certain motile responses. Expression profiling analysis revealed that a primary role of RSK is to induce transcription of a potent promotile/invasive gene program by FRA1-dependent and -independent mechanisms. The program enables RSK to coordinately modulate the extracellular environment, the intracellular motility apparatus, and receptors mediating communication between these compartments to stimulate motility and invasion. These findings uncover a mechanism whereby the RAS-ERK pathway controls epithelial cell motility by identifying RSK as a key effector, from which emanate multiple highly coordinate transcription-dependent mechanisms for stimulation of motility and invasive properties.
authors.affiliation: Biotech Research & Innovation Centre (BRIC) and Centre for Epigenetics, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Doehn
authors.forename: Camilla
authors.initials: C
authors.lastname: Hauge
authors.forename: Scott R
authors.initials: SR
authors.lastname: Frank
authors.forename: Claus J
authors.initials: CJ
authors.lastname: Jensen
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Duda
authors.forename: Jakob V
authors.initials: JV
authors.lastname: Nielsen
authors.forename: Michael S
authors.initials: MS
authors.lastname: Cohen
authors.forename: Jens V
authors.initials: JV
authors.lastname: Johansen
authors.forename: Benny R
authors.initials: BR
authors.lastname: Winther
authors.forename: Leif R
authors.initials: LR
authors.lastname: Lund
authors.forename: Ole
authors.initials: O
authors.lastname: Winther
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
authors.forename: Steen H
authors.initials: SH
authors.lastname: Hansen
authors.forename: Morten
authors.initials: M
authors.lastname: Frödin
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D054338:Cell Transdifferentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004285:Dogs; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D008648:Mesoderm / Q000201:enzymology / Q000473:pathology; D009361:Neoplasm Invasiveness; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D018631:ras Proteins / Q000378:metabolism*; D000099169:Fos-Related Antigen 1
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D016760:Proto-Oncogene Proteins c-fos; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D018631:ras Proteins; D000099169:Fos-Related Antigen 1; C069329:RPS6KA1 protein, human; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3