Nature Cell Biology 8, 571 - 580 (2006)
Published online: 14 May 2006; | doi:10.1038/ncb1418
A global analysis of cross-talk in a mammalian cellular signalling networkMadhusudan Natarajan1, 2, Keng-Mean Lin1, 2, Robert C. Hsueh1, 2, Paul C. Sternweis1, 2
& Rama Ranganathan1, 31
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390–-9050, USA. 2
The Alliance for Cellular Signalling, University of Texas Southwestern Medical Center, Dallas TX 75390, USA. 3
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390–9050, USA.
Correspondence should be addressed to Rama Ranganathan rama.ranganathan@utsouthwestern.edu Cellular information processing requires the coordinated activity of a large network of intracellular signalling pathways. Cross-talk between pathways provides for complex non-linear responses to combinations of stimuli, but little is known about the density of these interactions in any specific cell. Here, we have analysed a large-scale survey of pathway interactions carried out by the Alliance for Cellular Signalling (AfCS) in RAW 264.7 macrophages. Twenty-two receptor-specific ligands were studied, both alone and in all pairwise combinations, for Ca2+ mobilization, cAMP synthesis, phosphorylation of many signalling proteins and for cytokine production. A large number of non-additive interactions are evident that are consistent with known mechanisms of cross-talk between pathways, but many novel interactions are also revealed. A global analysis of cross-talk suggests that many external stimuli converge on a relatively small number of interaction mechanisms to provide for context-dependent signalling.
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