MAP2K4/MEK4

MAP2K4/MEK4, also called MKK4, is a dual-specificity MAP kinase kinase that activates JNK and p38 MAPK, but not ERK, placing it in stress-responsive MAPK signaling^[1][2]. Mechanistically, MAP2K4 functions downstream of MEKK-related inputs and connects stress signals to JNK/p38-dependent apoptosis, hepatogenesis, and cellular stress adaptation^[1][3]. In mouse models, SEK1/MKK4 deficiency causes abnormal liver formation, embryonic lethality, and liver cell apoptosis, supporting its use in developmental and liver biology studies^[3][4]. In cancer models, MAP2K4 shows context-dependent relevance: it promotes human prostate cancer metastasis in one experimental system, while MAP3K1 or MAP2K4 loss-of-function mutations predict MEK-inhibitor sensitivity in patient-derived xenografts^[5][6]. Compared with MKK7/MAP2K7, MAP2K4 is distinguished by broader substrate activity because MKK4 can activate p38 MAPK, whereas MKK7 functions as a more specific JNK activator^[7]. For experimental applications, first-in-class MKK4 inhibitors increased liver regeneration after hepatectomy in murine and porcine models, and MAP2K4 inhibition enhanced responses to RAS inhibitors in KRAS-mutant cancer cells^[8][9].