Mitogen-activated protein kinase kinase kinase 3 is an enzyme that in humans is encoded by the MAP3K3 gene, which is located on the long arm of chromosome 17 (17q23.3). This gene product is a 626-amino acid polypeptide that is 96.5% identical to mouse MEKK3. Its catalytic domain is closely related to those of several other kinases, including mouse MEKK2, tobacco NPK, and yeast STE11. MAP3Ks are involved in regulating cell fate in response to external stimuli. MAP3K3 directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NF-κB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed. MEKK3 regulates the p38, JNK and ERK1/2 pathways.