A systems biological approach suggests that transcriptional feedback regulation by dual-specificity phosphatase 6 shapes extracellular signal-related kinase activity in RAS-transformed fibroblasts.
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.
Blüthgen
Nils
N
Institute for Theoretical Biology, Humboldt University, Berlin, Germany. nils.bluethgen@charite.de
Legewie
Stefan
S
Kielbasa
Szymon M
SM
Schramme
Anja
A
Tchernitsa
Oleg
O
Keil
Jana
J
Solf
Andrea
A
Vingron
Martin
M
Schäfer
Reinhold
R
Herzel
Hanspeter
H
Sers
Christine
C
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
D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases; D054642:Dual Specificity Phosphatase 6