Members of the MAP3K family MLKs activate stress-dependent JNK and p38MAP kinase pathways in vitro. MLKs have been classified to the Ser/Thr MAP3Ks family. The sequence homology of their kinase domains demonstrates similarity to both Ser/Thr and Tyr kinases. MLK orthologs are relatively conserved across different species: for example, in Drosophila, MLK homolog Slpr is also an activator of JNK. There are three subfamilies comprised of seven members of the MLK family that have thus far been identified in mammals: the MLK core group, the DLK group, and the ZAK group. The MLK core group members possess a kinase domain flanked by a SRC homology 3 (SH3) domain on its N-terminus, and a leucine – zipper domain on the C-terminus which is followed by a Cdc42/Rac interactive binding, or CRIB (Cdc42- and Rac-interactive binding), domain. Four isoforms constitute this group: MLK1, 2, 3 and 4. Both MLK and TAK have been demonstrated to activate p38 and JNK MAPK in response to TNF. In mouse models of sepsis removing MLK2/3 significantly reduced cytokines and chemokines production (e.g. TNF, Ccl3 and Ccl5) and improved survival, which was mediated by the Rac/Cdc42 group of GTPases which works as a molecular switch to regulate MLK2/3 activity in response to inflammation through Src and Vav as a mediator, thus suggesting MLK2/3 may be a viable target for inflammation and autoimmune diseases.

References

1.Craige SM,et al. Biochim Biophys Acta. 2016;1862(9):1581–1586.