Extracellular Regulated Kinases 1/2 (ERK1/2) belong to the MAPK family and are critical for the cell's responses to a variety of stimuli. The Erk pathway is particularly essential for mediating growth factor signaling and is found to be abnormally overactive in almost all human cancers. Although all oncogenic mutations in the pathway result in strong activation of Erks, activating mutations in Erks themselves were not reported in cancers. Recently we identified a point mutation in Erks, a conversion of arginine residue located within the αC-helix in Erks, to Ser, which was sufficient to grant Erks independence of it's upstream activator and also rendered Erk1 (but not Erk2) oncogenic. Here we describe a thorough analysis of the mutated Arg. We show that it is invariant within all members of the MAPK family and distinguishes them from other protein kinases. It may be a key component in determining their catalytic and physiological properties, by functioning as a blocker of Erks' autophosphorylation ability. Investigating the mechanism behind the oncogenicity of Erk1R84S in living cells, it was found that following initial steps of activity, its activity is down-regulated via a dramatic feedback mechanism. It could be re-activated when cells are treated with erk inhibitors, suggesting re-evaluation of the strategy of using anti Erk inhibitors for therapy.
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