PP2C family members play key roles in regulation of cell survival and apoptosis.

Although unlimited proliferation of cancer cells is supported by multiple signaling pathways involved in the regulation of proliferation, survival, and apoptosis, the molecular mechanisms coordinating these different pathways to promote the proliferation and survival of cancer cells have remained unclear. SAPK and integrin-ILK signaling pathways play key roles in the promotion of apoptosis and cell proliferation/survival, respectively. Studies of TNFalpha- and H2O2-induced apoptosis revealed that ASK1, a component of the SAPK system, mediates the TNFalpha and H2O2 signaling of apoptosis. ASK1 is activated by autophosphorylation of a specific threonine residue (T845) following TNFalpha stimulation. Our recent studies indicate that PP2Cepsilon, a member of the PP2C family, associates with and inactivates ASK1 by dephosphorylating T845. In contrast, PP2Cdelta/ILKAP, a second PP2C family member, activates ASK1 by enhancing cellular phosphorylation of T845. PP2Cdelta/ILKAP also forms a complex with ILK1 to inhibit the GSK3beta-mediated integrin-ILK1 signaling in vivo, inhibiting cell cycle progression. These observations raise the possibility that PP2Cdelta/ILKAP acts to control the cross-talk between integrin-induced and TNFalpha-induced signaling pathways, inhibiting the former and stimulating the latter, thereby inhibiting proliferation and survival and promoting the apoptosis of cancer cells.