Reassessing the MAP3K and MAP4K relationships

MAPK cascades classically involve a MAPK, a MAP2K, a MAP3K and sometimes an upstream MAP4K. The 'MAP3K' and 'MAP4K' terminology is derived from their ability to phosphorylate MAP2Ks and MAP3Ks, respectively. Conversely, the sequences of protein kinases have been used to arrange these enzymes into phylogenetic and relationship trees. Both nomenclatures, based on species-specific trees (such as yeast, human, Caenorhabditis elegans and Arabidopsis), introduce discrepancies. MAP3Ks belong to two distant clades: the Raf superfamily and the STE family. Moreover, the 'MAP3K' and 'MAP4K' subfamilies observed on the relationship trees contain many members that do not function in the central core of a MAPK module. The terms 'MAP3K' and 'MAP4K' refer to phylogenetic similarity and not necessarily to biochemical function.