MKK

The mitogen-activated protein kinase kinase (MKK) signaling pathways are a group of related protein kinase signaling cascades that are widely expressed in eukaryotes including fungi, plants, and animals [67,68,69,70,71]. For epistemological reasons, MKK signaling pathways have been organized into modules, each of which contains a three-tiered kinase cascade comprising a mitogen-activated protein kinase kinase kinase (MAPKKK, MEKK, or MKKK), a mitogen-activated protein kinase kinase (MAPKK, MEK, or MKK), and a mitogen-activated protein kinase (MAPK). In response to extracellular stimuli such as growth factors or cytokines, ligand:receptor binding initiates activation of MKKK that phosphorylates MKK, which in turn phosphorylates MAPK. Phosphorylated/activated MAPK then phosphorylates effector molecules that may act at the transcriptional, post-transcriptional, or post-translational levels. The most extensively studied vertebrate MAPKs to date are the extracellular signal-regulated kinases (ERK 1 and 2) that are activated by MEK1 and 2; the p38 MAPK that are activated by MKK 3 and 6; and the jun kinases (JNK) that are activated by MKK4 and 7. More recently, ERK5, a target of MEK5, has emerged as a focus of interest.

Numerous in vitro studies have linked MKK signaling to both the transcriptional and the post-translational regulation of vital cellular processes, including cell differentiation, proliferation, motility, and survival. By contrast, only a handful of studies have attempted to address the functions of these signaling pathways in vivo, and fewer yet have considered the complex biology that may arise as a consequence of cross-talk between these pathways within a cell, tissue, organ, or whole organism.