Biology subjects

Kuchenov, D.

Publications and source records attributed to Kuchenov, D..

2 recordsLinked to original sources

bioRxiv2025

A quantitative approach to discover nonlinear signaling linking combinatorial environments with cellular responses

Cells constantly integrate diverse inputs from the extracellular environment, yet our understanding of how cells effectively process information from multiple cues at the same time remains limited. We utilized an integrated imaging platform and RNAseq analysis to investigate the combined effects of growth factors on cellular signaling and gene expression. Paired stimuli by receptor ligands revealed diverse signaling signatures-- ranging from antagonism to synergy--driving global signaling programs and gene expression. Notably, correlation networks based on signaling signatures identified vulnerabilities in cancer cells when compared to synergistic drug combinations. Profiling kinase and phosphatase activities uncovered a crucial interplay, where cellular sensitivity and phospho-turnover dynamics are modulated by input history through coordinated basal kinase and phosphatase activities. Our novel methodology sheds light on cellular processing of multiple cues, elucidating intricate mechanisms underlying cellular adaptation to extracellular environmental variations. Based on previous preprint: doi: https://doi.org/10.1101/346957

cell biology↗

bioRxiv2018

A combinatorial extracellular code tunes the intracellular signaling network activity to distinct cellular responses

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.

cell biology↗