MAP3K4 is a mitogen-activated protein kinase kinase kinase that functions as a key signaling node in multiple biological contexts. Mechanistically, MAP3K4 activates the JNK and p38 MAPK pathways through phosphorylation of MAP2K4 and MAP2K6, while notably sparing the ERK pathway 1. In developmental biology, MAP3K4 promotes fetal and placental growth by controlling IGF1R/IR and Akt signaling through activation of CREB-binding protein 1. MAP3K4 kinase inactivation results in fetal growth restriction and placental insufficiency 1. MAP3K4 also regulates HDAC6 and TRAF4 expression in trophoblast stem cells, with loss of MAP3K4 kinase activity leading to increased HDAC6 expression and altered TRAF4 stability 2. In neurological contexts, MAP3K4 controls neuroimmune signaling pathways including NF-κB and IRF3, orchestrating reactive gliosis and neurodegeneration through GADD45G-mediated signaling 3. Disease associations include germline truncation variants in ovarian cancer 4, recurrent mutations in Wilms tumors 5, and genetic polymorphisms associated with schizophrenia susceptibility 6. Additionally, MAP3K4 inhibition enhances stem-like properties in CAR T cells, promoting sustained antitumor effects 7. These findings establish MAP3K4 as a pleiotropic kinase with critical roles in development, immunity, and cancer biology.