Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade through the phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7 which in turn activate the JNKs. The MKK/JNK signaling pathway regulates stress response via activator protein-1 (JUN) and GATA4 transcription factors. Also plays a role in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein] Homodimerization via the leucine zipper domains is required for autophosphorylation of multiple sites in the activation loop and subsequent activation. Autophosphorylation at Thr-312 is the key step in activation of MAP3K9/MLK1 and is required for full phosphorylation. Autophosphorylation at Thr-304 and Ser-308 have been shown to be of secondary importance in the activation of MAP3K9/MLK1. CEP-1347 and many indolocarbazole analogs have been shown to act as inhibitors of MAP3K9/MLK1 activity. Homodimer. Expressed in epithelial tumor cell lines of colonic, breast and esophageal origin. Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation. Thr-312 is likely to be the main autophosphorylation site. Autophosphorylation also occurs on Thr-304 and Ser-308. May play a role in esophageal cancer susceptibility and/or development. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. Truncated N-terminus.