Dual-specificity mitogen-activated protein kinase kinases can use ADP to phosphorylate MAP kinases invitro.

Kinases are a diverse group of enzymes that use ATP to phosphorylate a variety of substrates. Protein kinases evolved in eukaryotes as important mediators of cell signaling that target specific amino acid side chains to modulate downstream protein function. Among them, the mitogen-activated protein kinases (MAPKs) are a family of intracellular protein kinases that form signaling cascades responding to a number of stimuli, which control fundamental mechanisms such as proliferation, differentiation, inflammation, and cell death. Signals propagate through consecutive kinases which eventually phosphorylate and activate a MAPK. Here, we show that the dual-specificity threonine/tyrosine mitogen-activated protein kinase kinases (MAP2Ks or MEKs) are able to phosphorylate and activate their substrate MAPKs using ADP as well as ATP in vitro. As the pathways are involved in the stress response, we speculate that it would represent an advantage to be able to maintain signaling under conditions such as hypoxia, which occur under a number of cell stresses, including cancer and atherosclerosis, where the available pool of ATP could be depleted.