The MAP2Ks can use ADP to phosphorylate and activate their substrate MAPKs in vitro

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 signalling that target specific amino acid side chains to modulate downstream protein function. Among them, the MAPKs (mitogen-activated protein kinases) are a family of intracellular protein kinases that form signalling cascades responding to a number of stimuli, that 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 MAP 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 signalling under conditions such as hypoxia, that occur under a number of cell stresses, including cancer and atherosclerosis, where the available pool of ATP could be depleted.

Highlights

• The MAP2K dual-specificity protein kinases can phosphorylate their target MAPKs using ADP in vitro

• The reaction with ADP is less efficient than with ATP

• First example of an enzyme that can use both ATP and ADP

• ADP phosphorylation might be a potential mechanism to maintain signal integrity when cell energy resources are constrained, as during ischemia