Protein phosphatase 2C (PP2C) is a Mn2+- or Mg2+-dependent protein serine/threonine phosphatase that inhibits the human stress-responsive p38 and JNK MAPK pathways and regulates cellular stress response in eukaryotes. The PPM(metal-dependent protein phosphatase) family of Ser/Thr protein phosphatases have recently been shown to down-regulate the stress response pathways in eukaryotes. Within the stress pathway, key signaling kinases, which are activated by protein phosphorylation, have been proposed as the in vivo substrates of PP2C, the prototypical member of the PPM family.