| MAP kinase interaction networks, in which component proteins can be seen as nodes, and the interactions between them links, or node connections, are evolutionarily stable. The network architecture, with the MAP kinases at its core, has been conserved from yeast to humans. The conserved CD/7m domain on MAP kinases facilitates binding to D-site containing proteins including upstream effectors, scaffolds, MAPK phosphatases and substrates. In yeast, mutating this region diminishes binding to the entire interaction network, the MEK Ste7, the scaffold Ste5, the transcription factor Ste12, and the transcriptional repressors Dig1 and Dig2. Weakening the MAPK interactions decreased signal flux through the pathway causing multiple defects in pheromone response. The CD/7m region on yeast MAPKs provides a tether to make strong node connections and thus preserving network robustness.; Evolving into a multicellular organism meant an increase in genome size going from 5000--6000 orfs in yeast to 30,000--35,000 in humans. To overcome the inevitable increase in interaction partners while keeping the network intact, node connections have evolved to be made up of different component tethers. D-sites bind to the CD/7m region and the hydrophobic docking groove. MITF binds to ERK2 with high affinity using a 100 residue region as a connection tether and does not bind to the CD/7m region, implying that it may bind to a different region of MAPKs. The ERK binding domain is structurally different than a D-site but serves the same purpose. The EBD is necessary and sufficient for binding to ERK2 with high affinity and it increases the ability of ERK2 to phosphorylate MITF. This shows that the node connections can be made up of different component tethers yet be functional equivalents. This may explain why D-site peptides preferentially inhibit phosphorylation of D-site containing substrates versus MITF.; The network architecture is made up of the MAP kinases and the high affinity interactions in which it involved. The nodes downstream vary, the nature of the high affinity interaction varies, but these are the result of the evolutionarily stable network's ability to adapt to the progression from a single cell to a multicellular organism. |
