Complex systems biology approach to understanding coordination of JAK-STAT signaling.
In this work, we search for coordination as an organizing principle in a complex signaling system using a multilevel hierarchical paradigm. The objective is to explain the underlying mechanism of Interferon (IFN(gamma)) induced JAK-STAT (specifically JAK1/JAK2-STAT1) pathway behavior. Starting with a mathematical model of the pathway from the literature, we modularize the system using biological knowledge via principles of biochemical cohesion, biological significance, and functionality. The modularized system is then used as a basis for in silico inhibition, knockdown/deletion and perturbation experiments to discover a coordination mechanism. Our analysis shows that a module representing the SOCS1 complex can be identified as the coordinator. Analysis of the coordinator can then be used for the selection of biological experiments for the discovery of 'soft' molecular drug targets, that could lead to the development of improved therapeutics. The coordinator identified is also being investigated to determine its relationship to pathological conditions.
Soebiyanto
Radina P
RP
Case Complex Systems Biology Center, Department of Electrical Engineering and Computer Science, Case Western Reserve University, Cleveland, OH, USA.
Sreenath
Sree N
SN
Qu
Cheng-Kui
CK
Loparo
Kenneth A
KA
Bunting
Kevin D
KD
D000818:Animals; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism*; D008433:Mathematics; D008954:Models, Biological; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D049490:Systems Biology
D050791:STAT Transcription Factors; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma; D053612:Janus Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11