The calcineurin signaling network evolves via conserved kinase-phosphatase modules that transcend substrate identity

Mol Cell. 2014 Aug 7;55(3):422-435. doi: 10.1016/j.molcel.2014.05.012. Epub 2014 Jun 12.


To define a functional network for calcineurin, the conserved Ca(2+)/calmodulin-regulated phosphatase, we systematically identified its substrates in S. cerevisiae using phosphoproteomics and bioinformatics, followed by copurification and dephosphorylation assays. This study establishes new calcineurin functions and reveals mechanisms that shape calcineurin network evolution. Analyses of closely related yeasts show that many proteins were recently recruited to the network by acquiring a calcineurin-recognition motif. Calcineurin substrates in yeast and mammals are distinct due to network rewiring but, surprisingly, are phosphorylated by similar kinases. We postulate that corecognition of conserved substrate features, including phosphorylation and docking motifs, preserves calcineurin-kinase opposition during evolution. One example we document is a composite docking site that confers substrate recognition by both calcineurin and MAPK. We propose that conserved kinase-phosphatase pairs define the architecture of signaling networks and allow other connections between kinases and phosphatases to develop that establish common regulatory motifs in signaling networks.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites / physiology
  • Calcineurin / chemistry
  • Calcineurin / genetics
  • Calcineurin / metabolism*
  • Conserved Sequence
  • Evolution, Molecular
  • Gene Expression Regulation, Fungal
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Docking Simulation
  • Phosphorylation
  • Phylogeny
  • Proteomics
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Signal Transduction
  • Substrate Specificity


  • Saccharomyces cerevisiae Proteins
  • Mitogen-Activated Protein Kinases
  • Calcineurin