The evolution of the MAP kinase pathways: coduplication of interacting proteins leads to new signaling cascades

J Mol Evol. 1999 Nov;49(5):567-82. doi: 10.1007/pl00006578.


The MAP-kinase pathways are intracellular signaling modules that are likely to exist in all eukaryotes. We provide an evolutionary model for these signaling pathways by focusing on the gene duplications that have occurred since the divergence of animals from yeast. Construction of evolutionary trees with confidence assessed by bootstrap clearly shows that the mammalian JNK and p38 pathways arose from an ancestral hyperosmolarity pathway after the split from yeast and before the split from C. elegans. These coduplications of interacting proteins at the MAPK and MEK levels have since evolved toward substrate specificity, thus giving distinct pathways. Mammalian duplications since the split from C. elegans are often associated with divergent tissue distribution but do not appear to confer detectable substrate specificity. The yeast kinase cascades have undergone similar fundamental functional changes since the split from mammals, with duplications giving rise to central signaling components of the filamentous and hypoosmolarity pathways. Experimentally defined cross-talk between yeast pheromone and hyperosmolarity pathways is mirrored with corresponding cross-talk in mammalian pathways, suggesting the existence of ancient orthologous cross-talk; our analysis of gene duplications at all levels of the cascade is consistent with this model but does not always provide significant bootstrap support. Our data also provide insights at different levels of the cascade where conflicting experimental evidence exists.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / genetics
  • Evolution, Molecular*
  • Gene Duplication
  • Intracellular Signaling Peptides and Proteins
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Mammals
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / genetics*
  • Mitogen-Activated Protein Kinases / metabolism
  • Models, Genetic
  • Osmosis
  • Oxidative Stress
  • Pheromones / genetics
  • Phylogeny
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / physiology
  • Saccharomyces cerevisiae Proteins*
  • Signal Transduction
  • Spores, Fungal
  • Substrate Specificity


  • Intracellular Signaling Peptides and Proteins
  • Pheromones
  • Saccharomyces cerevisiae Proteins
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • STE20 protein, S cerevisiae
  • Mitogen-Activated Protein Kinase Kinases