Diverse physiological functions of MKK4 and MKK7 during early embryogenesis

Mitogen-activated protein kinase kinases (MAPKKs) are important components of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) signalling pathway. Two MAPKKs that are crucial transducers upstream of JNK signalling are MKK4 and MKK7. These two MAPKKs directly phosphorylate specific Tyr and Thr residues located in the activation loop of the JNK protein and activate this kinase in response to environmental stress, pro-inflammatory cytokines or developmental cues. Although much is known about the biochemical and structural bases of the catalytic mechanism of the MAPKKs, the regulation and physiological functions of these enzymes during early embryogenesis have remained a mystery until relatively recently. Studies employing a range of animal models have now revealed the essential roles that MAPKKs play in diverse developmental contexts, including in dorsoventral patterning, convergent extension and somitogenesis. Focusing primarily on extensive work done in mouse and zebrafish models, this review summarizes the functional properties of MKK4 and MKK7 during vertebrate and invertebrate development, and the mechanisms by which these kinases regulate multiple steps in the establishment of the body plan of an organism.