Protein kinase which is part of a non-canonical MAPK signaling pathway (PubMed:7983011, PubMed:8663324, PubMed:28111074). Activated by APOE, enhances the AP-1-mediated transcription of APP, via a MAP kinase signal transduction pathway composed of MAP2K7 and MAPK1/ERK2 and MAPK3/ERK1 (PubMed:28111074). May be an activator of the JNK/SAPK pathway. ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein] ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein] Homodimer (PubMed:8663324). Interacts with MBIP (By similarity). Behaves essentially as an integral membrane protein. Within the nervous system, predominantly expressed in neurons and enriched in synaptic terminals (PubMed:8663324). Expressed in brain, kidney, lung, heart, testis, gastrointestinal tract, stomach, liver and pancreas (PubMed:8769565, PubMed:7983011). Interacts with MBIP through the leucine-zipper motif. Autophosphorylated on Ser/Thr. Phosphorylated in cytosol under basal conditions and dephosphorylated when membrane-associated. The activity of MAP3K12 can be regulated through its proteasomal degradation. APOE, through a receptor-mediated mechanism, activates MAP3K12 by preventing its proteasomal degradation. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.