Mutations That Confer Drug-Resistance, Oncogenicity and Intrinsic Activity on the ERK MAP Kinases-Current State of the Art

Abstract

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.

Keywords: CD domain; ERK1; ERK2; MAPK kinase; Rolled; SCH772984; VRT-11E; sevenmaker.

Figure 1

The kinase fold of Erks is highly similar to that of other ePKs, but they possess additional, specific domains. Shown are the crystal structures of (A) PKA (PDB 1FMO), (B) unphosphorylated Erk2 (PDB 4S31) and (C) dually phosphorylated Erk2 (PDB 2ERK). All panels show a cartoon representation covered with a transparent molecular surface with important regions presented and colored accordingly. Note the L16 helix and MAPK insert, not present in PKA, and the DEF pocket that forms only in phosphorylated Erk2.

Figure 2

Unusual flexibility of the Arg65 residue at the αC-helix of different Erk2 crystal structures. 5 different crystal structures of Erk2 (PDB 1ERK, 4ERK, 4S31, 4GT3 and 5UMO) were superimposed and a zoom in into the αC-helix (colored in red) is presented. Arg65 is shown in sticks and the distance between the two extreme orientations is calculated.