PMC:1481596 / 21170-24380 JSONTXT

{"project":"2_test","denotations":[{"id":"16722537-14743216-1694489","span":{"begin":1163,"end":1164},"obj":"14743216"},{"id":"16722537-15287979-1694490","span":{"begin":1365,"end":1367},"obj":"15287979"}],"text":"TNFα/NF-κB signaling pathway\nTo illustrate the power of COD in elucidating the dynamics behind protein complexes, we consider the TNFα/NF-κB signaling pathway. The Nuclear Factor κB (NF-κB) family of transcription factors is activated in response to a diverse set of stress stimuli, which includes pro-inflammatory cytokines, e.g., TNFα. In vertebrates, this family includes p50, p52, Rel A, c-Rel, and Rel B, which bind to the DNA in a homo or heterodimeric fashion. The NF-κB activity is regulated by the IκB family of proteins via inhibitory ankyrin repeat domains. This family includes IκBα, IκBβ, and IκB∈. The precursors of p50 (p105) and p52 (pl00) also possess ankyrin repeat domains and thus act as inhibitors. These precursors can also form dimers with other members of the NF-κB family. The activation with the pro-inflammatory cytokine tumor necrosis factor TNFα triggers a signaling cascade, which, in particular, stimulates the activation of the IKKα, IKKβ, and IKKγ functional groups. The IKKs initiate a signal induced degradation of the inhibitors (IκBs), and subsequent nuclear translocation of the transcription factor. Recent TAP experiments [5] provide a wealth of new information regarding this important signaling pathway. Bouwmeester et al. identified 221 molecular associations, out of which only 80 where previously known. Gagneur et al. [16] applied modular decomposition to the network of these associations but the decomposition halted quickly at large non-decomposable modules.\nWe used the COD method to analyze the subnetwork spanning all the paths from NIK (NFκB-inducing kinase phosphorylating IKKα and IKKβ) with at most three edges. For the purpose of the analysis, we contracted all five members of NF-κB family into one node. As the resulting protein interaction network, shown in Figure 3(a), is chordal without weak siblings, functional groups correspond to maximal cliques in the network.\nFigure 3 TNFα/NF-κB Signaling Pathway. The TNFα/NF-κB signaling pathway. (a) The network. (b) The Tree of Complexes representation. The flow of action is visually represented by background colors: green for activators (IKKs) and yellow for inhibitors (IκBs, and p100). The NIK kinase is in the first functional group (A), together with all three members of the IKK complex and p100. Functional group B includes, in addition to p100, the IKKs and two inhibitors IκBα and IκBβ. This group is the beginning of interaction between IKKs and IκBs. Functional group C loses some of the IKKs, continues to show IκB and begins to show interaction between IκBs and NF-κB factors. Finally, in group E we see the entrance of NIK-independent Col-Tpl2 kinase. For this network, there are two alternative Tree of Complexes representations: functional group E can be connected to either D or C. The representation that maximizes the number of leaves is shown in Figure 3(b). One can clearly see the interplay between the activators and inhibitors. Proteins p105 and NF-κB participate in the same functional groups and thus follow the same path in the tree. The same is true for the pair of proteins IkBα and IkBβ. The Tree of Complexes captures this by grouping p105 and NF-κB, and IkBα and IkBβ."}