Mitogen-activated protein kinase kinase kinase 1 (MAP3K1)

Mitogen‐activated protein kinase kinase kinase 1 (MAP3K1) is a serine/threonine-protein kinase that acts at an upstream position within several major intracellular signaling cascades—including the ERK/MAPK pathway, JNK pathway, and NF-kappa-B pathway—by phosphorylating downstream kinases such as MAP2Ks. It contains both a catalytic domain responsible for its phosphotransferase activity and regulatory domains including a plant homeodomain (PHD) with E3 ubiquitin ligase function. Through these activities it regulates diverse cellular processes such as cell growth/proliferation, apoptosis/survival decisions, differentiation during embryonic development (notably eyelid closure), immune responses via NF-kappa-B activation, and transcriptional control through AP‐1 complex regulation. Germline or somatic mutations can result in developmental syndromes like disorders of sex development or contribute to cancer pathogenesis by dysregulating cell fate decisions.

Other names

MEKK1 (Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1)MAPKKK1M3K1

Drugs such as dasatinib inhibit the enzymatic activity of MAP3K1 by binding to its ATP-binding site or allosteric sites, thereby blocking downstream phosphorylation events within the ERK/JNK/NF-kappa-B signaling cascades.