title: A systems biological approach suggests that transcriptional feedback regulation by dual-specificity phosphatase 6 shapes extracellular signal-related kinase activity in RAS-transformed fibroblasts.
abstract: Mitogen-activated protein kinase (MAPK) signaling determines crucial cell fate decisions in most cell types, and mediates cellular transformation in many types of cancer. The activity of MAPK is controlled by reversible phosphorylation, and the quantitative characteristics of MAPK activation determine the cellular response. Many systems biological studies have analyzed the activation kinetics and the dose-response behavior of the MAPK signaling pathway. Here we investigate how the pathway activity is controlled by transcriptional feedback loops. Initially, we predict that MAPK signaling regulates phosphatases, by integrating promoter sequence data and ontology-based classification of gene function. From this, we deduce that MAPK signaling might be controlled by transcriptional negative feedback regulation via dual-specificity phosphatases (DUSPs), and implement a mathematical model to further test this hypothesis. Using time-resolved measurements of pathway activity and gene expression, we employ a model selection approach, and select DUSP6 as a highly likely candidate for shaping the activity of the MAPK pathway during cellular transformation caused by oncogenic RAS. Two predictions from the model were confirmed: first, feedback regulation requires that DUSP6 mRNA and protein are unstable; and second, the activation kinetics of MAPK are ultrasensitive. Taken together, an integrated systems biological approach reveals that transcriptional negative feedback controls the kinetics and the extent of MAPK activation under both physiological and pathological conditions.
authors.affiliation: Institute for Theoretical Biology, Humboldt University, Berlin, Germany. nils.bluethgen@charite.de
authors.forename: Nils
authors.initials: N
authors.lastname: Blüthgen
authors.forename: Stefan
authors.initials: S
authors.lastname: Legewie
authors.forename: Szymon M
authors.initials: SM
authors.lastname: Kielbasa
authors.forename: Anja
authors.initials: A
authors.lastname: Schramme
authors.forename: Oleg
authors.initials: O
authors.lastname: Tchernitsa
authors.forename: Jana
authors.initials: J
authors.lastname: Keil
authors.forename: Andrea
authors.initials: A
authors.lastname: Solf
authors.forename: Martin
authors.initials: M
authors.lastname: Vingron
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schäfer
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Herzel
authors.forename: Christine
authors.initials: C
authors.lastname: Sers
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054642:Dual Specificity Phosphatase 6 / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D049490:Systems Biology
chemical_list: D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases; D054642:Dual Specificity Phosphatase 6