The RTK/Ras/Raf cascade is overactive in cancers. Its targets are the MAP kinases Erks, but Erks are not mutated in cancers. An active Erk, Erk1(R84S), is an oncoprotein. Further, Erk1(R84S) and Erk2(R65S) autophosphorylate the TEY motif and Thr-207/Thr-188. Erk2(R65S) autophosphorylates Thr-188 when dually mutated in the TEY.

Unique characteristics distinguish extracellular signal-regulated kinases (Erks) from other eukaryotic protein kinases (ePKs). Unlike most ePKs, Erks do not autoactivate and they manifest no basal activity; they become catalysts only when dually phosphorylated on neighboring Thr and Tyr residues and they possess unique structural motifs. Erks function as the sole targets of the receptor tyrosine kinases (RTKs)-Ras-Raf-MEK signaling cascade, which controls numerous physiological processes and is mutated in most cancers. Erks are therefore the executers of the pathway’s biology and pathology. As oncogenic mutations have not been identified in Erks themselves, combined with the tight regulation of their activity, Erks have been considered immune against mutations that would render them intrinsically active. Nevertheless, several such mutations have been generated on the basis of structure-function analysis, understanding of ePK evolution and, mostly, via genetic screens in lower eukaryotes. One of the mutations conferred oncogenic properties on Erk1. The number of interesting mutations in Erks has dramatically increased following the development of Erk-specific pharmacological inhibitors and identification of mutations that cause resistance to these compounds. Several mutations have been recently identified in cancer patients. Here we summarize the mutations identified in Erks so far, describe their properties and discuss their possible mechanism of action.