A global analysis of cross-talk in a mammalian cellular signalling network

Nat Cell Biol. 2006 Jun;8(6):571-80. doi: 10.1038/ncb1418. Epub 2006 May 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling
  • Cluster Analysis
  • Cyclic AMP / biosynthesis
  • Cytokines / biosynthesis
  • Ligands
  • Macrophages
  • Mice
  • Phosphorylation
  • Receptor Cross-Talk*
  • Signal Transduction*


  • Cytokines
  • Ligands
  • Cyclic AMP