Complex systems biology approach to understanding coordination of JAK-STAT signaling

Abstract

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 γ ) 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.

Transient oscillatory dynamics of interferon beta signaling in macrophages

“…Our results show that a combination of positive and negative feedback loops, together with the eventual degradation of the IFN signal in the medium, leads to a transient oscillatory response in several components of the pathway. This behavior is consistent with previous numerical results found in pure modeling studies [13], and goes beyond previous observations that indicate a simpler transient response [10,14,15]. We interpret the transient oscillatory response of the pathway in terms of the potential effectiveness of IFN-beta treatment in MS patients.…”

Emerging role of leptin in rheumatoid arthritis

“…Tyr985-phosphorylated STAT-3 is separated from lepRb, dimerizing and entering the nucleus. STAT-3 dimers, as a transcription factor, adjust the expression of targeting genes such as suppressor of cytokine signalling 3 (SOCS3) and neuropeptides [65][66][67]. There is another way to mediate JAK2 signalling: after leptin stimulation of lepRb phosphorylation on Tyr1077, a combination phosphoTyr1077 with the SH2 domain of STAT-5 allows STAT-5 phosphorylation and activation by JAK2 [68].…”

Understanding inhibition of viral proteins on type I IFN signaling pathways with modeling and optimization

“…The IFN related signaling pathways are very important and have attracted the attention of many researchers including some modelers (Beirer and Hofer, 2006;Li et al, 2009b;Sadler and Williams, 2008;Smieja et al, 2008;Soebiyanto et al, 2007;Taniguchi and Takaoka, 2001;Taniguchi and Takaoka, 2002;Yamada et al, 2003;Zi et al, 2005). In recent years, mathematical modeling and theoretic analysis were used to investigate the control mechanism and to identify the coordination of IFNinduced JAK-STAT signaling pathways (Beirer and Hofer, 2006;Smieja et al, 2008;Soebiyanto et al, 2007;Yamada et al, 2003;Zi et al, 2005). To our best knowledge, the modeling of signaling pathways of virus-mediated IFN induction has not been reported in the literature.…”

“…However, it remains unclear if there exist potential antagonizing networks and a synergistic inhibitory effect from various proteins encoded by CSFV for antagonizing IFN-b induction. Many studies have demonstrated that system-level analysis of signaling pathways have the power to get new insights into cell signaling networks (Adler et al, 2006;Chou et al, 2008;Klipp et al, 2005;Li et al, 2009a;Liu et al, 2008;Zou et al, 2008a). The IFN related signaling pathways are very important and have attracted the attention of many researchers including some modelers (Beirer and Hofer, 2006;Li et al, 2009b;Sadler and Williams, 2008;Smieja et al, 2008;Soebiyanto et al, 2007;Taniguchi and Takaoka, 2001;Taniguchi and Takaoka, 2002;Yamada et al, 2003;Zi et al, 2005). In recent years, mathematical modeling and theoretic analysis were used to investigate the control mechanism and to identify the coordination of IFNinduced JAK-STAT signaling pathways (Beirer and Hofer, 2006;Smieja et al, 2008;Soebiyanto et al, 2007;Yamada et al, 2003;Zi et al, 2005).…”