The mitogen-activated protein kinase cascade is a conserved signal transduction pathway found in organisms of complexity spanning from yeast to humans. contributes to the overall specificity of the gene expression output and hypothesize that this RU 58841 complicated nature of the mammalian mitogen-activated protein kinase pathway results in a system able to robustly identify and transduce the proper signal without investing in two completely individual signal cascades. Finally we quantify the role from the RKIP proteins in shaping the sign and propose a book system of its participation in cancer metastasis. Introduction One of the most fascinating questions in cellular biology is how a signal transduction network with one or more RU 58841 shared components can accurately transmit multiple impartial signals from the cell surface to their proper targets (nucleus vacuoles cytoskeletal junctions etc.). Often the subcellular localization of the signal target is the same but the distinct signals elicit very different outcomes. The best studied of this phenomenon is the PC-12 model system (1-3). PC-12 cells are RU 58841 rat-derived neural progenitor cells that can be induced to proliferate upon epidermal growth factor (EGF) stimulation or to differentiate upon neural growth factor (NGF) stimulation (3). In both cases the signal is usually transduced through the mitogen-activated protein kinase cascade (MAPK) of Raf Mek and Erk (4 5 While some of the biological details about how this pathway works and exactly how it progressed remain unclear an over-all structure for pathway specificity continues to be uncovered. When activated with EGF Computer-12 cells display a transient spike in Raf Mek and Erk activity which quickly dies out back again to background RU 58841 amounts. Induction with NGF causes a transient spike equivalent in magnitude and duration however in comparison to EGF excitement the spike decays just partway resulting in a long-term steady degree of Erk activity many hours following the preliminary stimulus pulse Mouse monoclonal to CD8 (3 5 In RU 58841 the current presence of an NGF sign there’s a positive responses force performing from Erk to Raf stabilizing Raf in its energetic verification (2 3 6 This responses mechanism is certainly suppressed under EGF signaling. The main element mediator of the suppression was defined as RKIP a known inhibitor of Raf kinase activity (3 6 7 This RU 58841 proteins appears to not merely competitively stop Raf’s capability to activate Mek but also through steric or various other forces stop Erk’s capability to phosphorylate Raf. The functioning hypothesis is a supplementary signaling pathway is certainly turned on upon NGF arousal resulting in a deactivation of RKIP and therefore enhancement from the positive reviews loop. Many hypotheses regarding the next thing of the procedure how the instant early genes (IEG) react to transient and suffered Erk activity are also proposed (8); nevertheless the information on gene appearance in response towards the IEG activity aren’t known. We hypothesize that indication transduction systems are optimized to keep the specificity of confirmed indication insight in a solid way. An abstract description of specificity is certainly provided in Komarova et?al. (9) to end up being the proportion of the right result towards the spurious output of a signaling network relative to a given input stimulus. This definition was then applied to several simple network architectures including multiple inputs and outputs but at least one shared component can be tuned to generate specificity under general conditions around the network connection strengths and the character of the input stimuli. Later work applied these abstractions to networks including scaffolding and cross-network inhibition (10). These definitions have also been used to analyze the yeast pheromone and stress response pathways (11). In this work we extend this concept of specificity to include robustness which we define as a network’s ability to properly interpret a wide range of transmission input profiles into the proper temporal output. There is growing desire for investigating more complex mammalian transmission transduction pathways using theoretical and computational methods. The classic Raf-Mek-Erk MAPK cascade has drawn much interest especially concerning receptor activation (12 13.