Signal transduction cascade from TNF ligands to transcription factors reconstructed by ExPlain™ system. TNF ligand is depicted as orange triangle. Transcription factors (TFs, diamonds) are identified by promoter analysis of up-regulated genes upon TNF-alpha stimulation of HUVEC cell line. Dashed arrows represent the novel predicted kinase-substrate interactions helping to connect TNF ligands with TFs through cascades of phosphorylation events. All other arrows represent signal transduction interactions known in TRANSPATH®. The up-regulated molecules are red. The down-regulated molecules are green. Two underlined TFs can be reached from TNF ligands in less than 6 steps with the help of the novel kinase-substrate interactions only.