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RISS 인기검색어
- 검색키워드
- 저자 : ( Walter Kolch ) (검색결과 4 건)
- 무료
- 기관 내 무료
- 유료
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Multiple roles of the NF‐?B signaling pathway regulated by coupled negative feedback circuits
Kim, Dongsan,Kolch, Walter,Cho, Kwang-Hyun Federation of American Society for Experimental Bi 2009 The FASEB Journal Vol.23 No.9
<P>The NF-kappaB signaling pathway can perform multiple functional roles depending on specific cellular environments and cell types. Even in the same cell clones, the pathway can show different kinetic and phenotypic properties. It is believed that the complex networks controlling the NF-kappaB signaling pathway can generate these diverse and sometimes ambiguous phenomena. We noted, however, that the dynamics of NF-kappaB signaling pathway is highly stochastic and that the NF-kappaB signaling pathway contains multiple negative feedback circuits formed by IkappaB isoform proteins, IkappaBalpha and IkappaBepsilon in particular. Considering the topological similarity, their functional roles seem to be redundant, raising the question why different types of IkappaB isoforms need to exist. From extensive stochastic simulations of the NF-kappaB signaling pathway, we found that each IkappaB isoform actually conducts a different regulatory role through its own negative feedback. Specifically, our data suggest that IkappaBalpha controls the dynamic patterns of nuclear NF-kappaB, while IkappaBepsilon induces cellular heterogeneity of the NF-kappaB activities. These results may provide an answer to the question of how a single NF-kappaB signaling pathway can perform multiple biological functions even in the same clonal populations.</P>
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Robustness and Evolvability of the Human Signaling Network
Kim, Junil,Vandamme, Drieke,Kim, Jeong-Rae,Munoz, Amaya Garcia,Kolch, Walter,Cho, Kwang-Hyun Public Library of Science 2014 PLoS computational biology Vol.10 No.7
<▼1><P>Biological systems are known to be both robust and evolvable to internal and external perturbations, but what causes these apparently contradictory properties? We used Boolean network modeling and attractor landscape analysis to investigate the evolvability and robustness of the human signaling network. Our results show that the human signaling network can be divided into an evolvable core where perturbations change the attractor landscape in state space, and a robust neighbor where perturbations have no effect on the attractor landscape. Using chemical inhibition and overexpression of nodes, we validated that perturbations affect the evolvable core more strongly than the robust neighbor. We also found that the evolvable core has a distinct network structure, which is enriched in feedback loops, and features a higher degree of scale-freeness and longer path lengths connecting the nodes. In addition, the genes with high evolvability scores are associated with evolvability-related properties such as rapid evolvability, low species broadness, and immunity whereas the genes with high robustness scores are associated with robustness-related properties such as slow evolvability, high species broadness, and oncogenes. Intriguingly, US Food and Drug Administration-approved drug targets have high evolvability scores whereas experimental drug targets have high robustness scores.</P></▼1><▼2><P><B>Author Summary</B></P><P>Biological systems are known to be robust and evolvable to internal mutations and external environmental changes. What causes these apparently contradictory properties? This study shows that the human signaling network can be decomposed into two structurally distinct subgroups of links that provide both evolvability to environmental changes and robustness against internal mutations. The decomposition of the human signaling network reveals an evolutionary design principle of the network, and also facilitates the identification of potential drug targets.</P></▼2>
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Shin, Sung-Young,Rath, Oliver,Choo, Sang-Mok,Fee, Frances,McFerran, Brian,Kolch, Walter,Cho, Kwang-Hyun Cambridge University Press 2009 Journal of cell science Vol.122 No.3
<P>The Ras-Raf-MEK-ERK pathway (or ERK pathway) is an important signal transduction system involved in the control of cell proliferation, survival and differentiation. However, the dynamic regulation of the pathway by positive- and negative-feedback mechanisms, in particular the functional role of Raf kinase inhibitor protein (RKIP) are still incompletely understood. RKIP is a physiological endogenous inhibitor of MEK phosphorylation by Raf kinases, but also participates in a positive-feedback loop in which ERK can inactivate RKIP. The aim of this study was to elucidate the hidden dynamics of these feedback mechanisms and to identify the functional role of RKIP through combined efforts of biochemical experiments and in silico simulations based on an experimentally validated mathematical model. We show that the negative-feedback loop from ERK to SOS plays a crucial role in generating an oscillatory behavior of ERK activity. The positive-feedback loop in which ERK functionally inactivates RKIP also enhances the oscillatory activation pattern of ERK. However, RKIP itself has an important role in inducing a switch-like behavior of MEK activity. When overexpressed, RKIP also causes delayed and reduced responses of ERK. Thus, positive- and negative-feedback loops and RKIP work together to shape the response pattern and dynamical characteristics of the ERK pathway.</P>
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