Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Phosphorylation by MAP2K6 asymmetrically activates p38 on one side of the blastodisc, an event which is necessary for blastomere cleavage. ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein] ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-[protein] Activated by dual phosphorylation on Ser-234 and Thr-238 in response to a variety of cellular stresses, including UV radiation, osmotic shock, hypoxia, inflammatory cytokines, interferon gamma (IFNG), and less often by growth factors. MAP2K6/MKK6 is activated by the majority of M3Ks (By similarity). Dimer. Interacts (via its D domain) with its MAP kinase substrates. Interacts (via its DVD domain) with MAP3Ks activators. Binds to microtubules. Expressed both maternally and zygotically. Zygotic expression continues throughout development. The DVD domain (residues 338-361) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation (By similarity). The D domain (residues 30-46) contains a conserved docking site and is required for the binding to MAPK substrates. Weakly autophosphorylated (By similarity). Phosphorylated at Ser-234 and Thr-238 by the majority of M3Ks. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. Was originally thought to be a Map2k3 protein but sequence analysis shows closer similarity to the Map2k6 proteins. Truncated N-terminus.