PT  - JOURNAL ARTICLE
AU  - Dmitry Kuchenov
AU  - Frederik Ziebell
AU  - Florian Salopiata
AU  - Mevlut Citir
AU  - Ursula Klingmueller
AU  - Wolfgang Huber
AU  - Carsten Schultz
TI  - A combinatorial extracellular code tunes the intracellular signaling network activity to distinct cellular responses
AID  - 10.1101/346957
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 346957
4099  - http://biorxiv.org/content/early/2018/06/14/346957.short
4100  - http://biorxiv.org/content/early/2018/06/14/346957.full
AB  - Cells constantly survey a complex set of inputs that is processed by the intracellular signaling network, but little is known of how cells integrate input information from more than one cue. We employed a FRET biosensor-based imaging platform to study the effect of combinatorial growth factor levels on the signaling network in human cells. We found that pairwise stimuli caused distinct concentration- and ratio-dependent signaling states through signaling signatures such as antagonism, additivity and synergy. The unique signaling states correlated with differential gene expression and non-additive transcription patterns. We further elucidated how a signal-rich environment can fine-tune the signaling network and adjust physiological outcomes, by kinase and phosphatase activity profiling. We describe how complex extracellular conditions affect phospho-turnover and the basal phosphorylation status. Thus, we provide mechanistic insights into cellular processing of multiple cues and explain part of the complexity of cellular adaptation to changes in the extracellular environment.