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Supplementary website - http://arep.med.harvard.edu/NetSearchWeb interface for NetSearch: http://arep.med.harvard.edu/NetSearch/runprog.html
The signaling network models generated by NetSearch for the pheromone response, cell wall integrity and filamentation pathways are depicted in Fig.
1shows that NetSearch reproduced many of the essential elements of these MAPK pathways, while providing a detailed account of the experimentally determined interconnections among network elements.
However, we emphasize that NetSearch selects paths based on their rank relative to all paths between selected starting and endpoints.
It includes Far1p, a protein necessary for pheromone-induced cell cycle arrest in G1 [ 11 ] , Mpt5p, a protein necessary for recovery from cell cycle arrest [ 12 ] , and Bem1p and Sph1, both of which are necessary for establishment of cell polarity during shmooing and budding [ 13 14 ] . In our protein-interaction map there is no direct interaction between a pheromone receptor (Ste2p or Ste3p) and any component of the heterotrimeric G protein complex (Ste4p/Ste18p/Gpa1p), so NetSearch drew indirect paths through Akr1p, a known inhibitor of signaling in the pheromone pathway [ 15 ] . The predicted network does not include the GTPase Cdc42p (paths were instead drawn preferentially through its cofactor Cdc24p, which physically interacts with Ste4p) or Ste20p, because of missing interactions in the protein-interaction map.