Abstract
Interleukin-1 mediates inflammation and stress response through nuclear activity of p38α. Although IL-1 receptor is not degraded, p38α activation is transient. IL-1 also causes cell migration and EMT by modulating cell-cell junctions. Although molecules involved in p38 activation are known, mechanism of the transient nuclear response and its basal activity remains unknown. By mathematical modeling of IL1/p38 signaling network, we show that IL-1 induces robust p38α activation both in the nucleus and in the cytoplasm/membrane. While nuclear response consists of an acute phase, membrane response resembles a step change. Following stimulation, p38α activity returns to a basal level in absence of receptor degradation. While nuclear pulse is controlled by MKP1 through a negative feedback to pp38, its basal activity is controlled by both TAB1 and MKP1 through a positive feedback loop. Our model provides insight into the mechanism of p38α activation, reason for its transient nuclear response, and explanation of the basal activity of MKK3/6 and p38α, which has been experimentally observed by other groups.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Amino Acid Sequence / genetics
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Cell Movement / genetics
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Cytoplasm / enzymology
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Enzyme Activation / genetics
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Feedback, Physiological
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Humans
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Inflammation / enzymology
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Inflammation / genetics*
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Inflammation / pathology
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Intercellular Junctions / genetics
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MAP Kinase Kinase 3 / genetics
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Mitogen-Activated Protein Kinase Phosphatases / genetics*
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Models, Theoretical
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Nuclear Envelope / enzymology
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Phosphorylation
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Signal Transduction
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Stress, Physiological / genetics*
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p38 Mitogen-Activated Protein Kinases / biosynthesis*
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p38 Mitogen-Activated Protein Kinases / genetics
Substances
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Adaptor Proteins, Signal Transducing
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TAB1 protein, human
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 3
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MAP2K3 protein, human
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Mitogen-Activated Protein Kinase Phosphatases
Grants and funding
This work was supported by Indian Institute of Technology Kanpur grant IITK/CHE/20090282 to RS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.