MEK kinase 1 gene disruption alters cell migration and c-Jun NH2-terminal kinase regulation but does not cause a measurable defect in NF-kappa B activation

MEK kinase 1 (MEKK1) is a 196-kDa mitogen-activated protein kinase (MAPK) k inase kinase that, in addition to regulating the c-Jun NH2-terminal kinase (JNK) pathway, is involved in the control of cell motility. MEKK1(-/-) mice are defective in eyelid closure, a TGF alpha-directed process involving th e migration of epithelial cells. MEKK1 expression in epithelial cells stimu lates lamellipodia formation, a process required for cell movement. In addi tion, mouse embryo fibroblasts derived from MEKK1(-/-) mice are inhibited i n their migration relative to MEKK1(+/+) fibroblasts. MEKK1 is required for JNK but not NF-kappa B activation in response to virus infection, microtub ule disruption, and stimulation of embryonic stem cells with lysophosphatid ic acid. MEKK1 is not required for TNF alpha or IL-1 regulation of JNK or N F-kappa B activation in macrophages or fibroblasts. Thus, MEKK1 senses micr otubule integrity, contributes to the regulation of fibroblast and epitheli al cell migration, and is required for activation of JNK but not NF-kappa B in response to selected stress stimuli.