Journal
BIOSYSTEMS
Volume 90, Issue 3, Pages 830-842Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biosystems.2007.05.005
Keywords
JAK-STAT; multilevel; hierarchical; coordination; systems biology; mathematical modeling
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Funding
- NCI NIH HHS [U56 CA 112963, U56 CA112963, K25 CA113133-01, K25 CA113133-02, K25 CA 113133, K25 CA113133-04, K25 CA113133, K25 CA113133-03] Funding Source: Medline
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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 JAKI/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 SOCS I 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. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
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