Model Predicts That MKP1 and TAB1 Regulate p38α Nuclear Pulse and Its Basal Activity through Positive and Negative Feedback Loops in Response to IL-1.
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.
Department of Chemical Engineering, Indian Institute of Technology Kanpur, Kanpur, India.
Raghvendra
R
Singh
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D003593:Cytoplasm / Q000201:enzymology; D004789:Enzyme Activation / Q000235:genetics; D025461:Feedback, Physiological; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D007365:Intercellular Junctions / Q000235:genetics; D048371:MAP Kinase Kinase 3 / Q000235:genetics; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics*; D008962:Models, Theoretical; D009685:Nuclear Envelope / Q000201:enzymology; D010766:Phosphorylation; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C486300:TAB1 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases