RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cells

TY - JOUR

T1 - RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cells

AU - Doehn, Ulrik

AU - Hauge, Camilla

AU - Frank, Scott R

AU - Jensen, Claus Antonio Juel

AU - Duda, Katarzyna

AU - Nielsen, Jakob V

AU - Cohen, Michael S

AU - Johansen, Jens V

AU - Winther, Benny R

AU - Lund, Leif R

AU - Winther, Ole

AU - Taunton, Jack

AU - Hansen, Steen H

AU - Frödin, Morten

N1 - Keywords: Animals; Carcinoma; Cell Line; Cell Movement; Cell Transdifferentiation; Cell Transformation, Neoplastic; Dogs; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genotype; Humans; Mesoderm; Neoplasm Invasiveness; Phenotype; Proto-Oncogene Proteins c-fos; Ribosomal Protein S6 Kinases, 90-kDa; Signal Transduction; Time Factors; Transcription, Genetic; Transduction, Genetic; ras Proteins

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1016/j.molcel.2009.08.002

DO - 10.1016/j.molcel.2009.08.002

M3 - Journal article

C2 - 19716794

SN - 1097-2765

VL - 35

SP - 511

EP - 522

JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -