Control mechanism of JAK/STAT signal transduction pathway

Abstract

Suppressor of cytokine signaling-1 (SOCS1) was identi¢ed as the negative regulator of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signal transduction pathway. However, the kinetics and control mechanism of the pathway have not yet been fully understood. We have developed the computer simulation of the JAK/STAT pathway. Without nuclear phosphatase, SOCS1's binding to JAK did not cause the decrease in nuclear phosphorylated STAT1. However, without SH2 domain-containing tyrosine phosphatase 2 (SHP-2) or cytoplasmic phosphatase, it did. So nuclear phosphatase is considered to be the most important in this system. By changing parameters of the model, dynamical characteristics and control mechanism were investigated.

Analysis of IL6 Signal Transduction Model using Reduced Rank Regression

“…From previous literature, the transition of STAT3 between the nucleus and the cytoplasm has been described as playing a crucial role in signal transduction [12] and this has been observed both in this analysis and the recent sensitivity analysis on the same model.…”

Multivariate statistical analysis applied to an IL6 signal transduction model in hepatocytes

“…The JAK/STAT pathway is considered to be one of the most important signalling pathways downstream of cytokine receptors [27] and can be activated by a wide variety of cytokines and growth factor signals [28]. The MAPK cascade is another important pathway widely involved in eukaryotic signal transduction [29].…”

Model Based Analysis of Signaling Pathways

“…Their role and elements of interferon induced signaling pathways are subjects of ongoing research (see, e.g., the reviews (Levy and Darnell, 2002;Sen, 2001;Pestka et al, 2004)) . However, there are very few attempts to model the processes involved in the signaling pathways activated by IFN, and they are mostly concerned with IFN-γ that is produced only by activated lymphocytes (Yamada et al, 2003;Zi et al, 2005). In this section, the mathematical model description of early processes activated by IFN-β, a cytokine produced by most cell types following viral infection, will be briefly introduced.…”

“…It should be stressed that there are at least several known phosphatases that are responsible for STAT dephosphorylation (Hoeve et al, 2002), and several others are postulated (Yamada et al, 2003). It would be extremely difficult, if possible at all, to conduct experiments in which specific phosphatases would be blocked.…”