The ? isoform of protein phosphatase 2C (PP2C-?) is the catalytic subunit of a widely expressed serine/threonine phosphatase involved in regulation of the cell stress response. Also known as magnesium-dependent protein phosphatase (PPM1A), this monomeric phosphatase is a member of a conserved group of proteins that acts on many different substrates in numerous pathways. PP2C-? inhibits p38 MAPK and SAPK/JNK pathways activated in response to cell stress as seen in both in vivo and in vitro studies. Specifically, PP2C-? removes phosphates from MKK3 and MKK7, reducing activity of both proteins and inhibiting activation of the downstream kinases JNK and p38 MAPK, respectively. Another PP2C-? substrate is IKK?, the critical regulator of NF-?B signaling. Dephosphorylation of IKK? at Ser177/181 by PPM1A and PPM1B results in inactivation of IKK? and inhibition of NF-?B signaling. PP2C-? is one of the phosphatases responsible for removing phosphate residues from cyclin dependent protein kinases. In a study using HeLa cell extracts, PP2C-? dephospohrylates CDK2 and CDK6, with a preference toward interacting with CDK2 phosphorylated at Thr160, a residue found in the activating T-loop of the kinase. Removal of phosphates from this site is thought to inactivate cyclin-associated kinases. PP2C-? induces cell cycle arrest and apoptosis, likely through activation of p53 though other pathways may also contribute to PP2C-? mediated cell death . Additional PP2C-? substrates include the Wnt signaling pathway protein axin and CFTR, a chloride channel protein implicated in cystic fibrosis.