MAP kinase kinase: a node connecting multiple pathways.

Numerous studies have been published these last few years on the involvement of MAP kinases in signal transduction reflecting their importance in cell cycle and cell growth controls. The identification and the characterization of their direct upstream activator has considerably enlarged our understanding of the phosphorylation network. The MAP kinase kinases (MAPKKs) are dual-specificity protein kinases which phosphorylate and activate MAP kinases. To date, MAPKK homologues have been found in yeast, invertebrates, amphibians, and mammals. Moreover, the MAPKK/MAPK phosphorylation switch constitutes a basic module activated in distinct pathways in yeast and in vertebrates. MAPKK regulation studies have led to the discovery of at least four MAPKK convergent pathways in higher organisms. One of these is similar to the yeast pheromone response pathway which includes the ste11 protein kinase. Two other pathways require the activation of either one or both of the serine/threonine kinase-encoded oncogenes c-Raf-1 and c-Mos. Additionally, recent studies suggest a possible effect of the cell cycle control regulator cyclin-dependent kinase 1 (cdc2) on MAPKK activity. Finally, MAPKKs seem to be essential transducers through which signals must pass before reaching the nucleus.