MEK kinase 1 is critically required for c-Jun N-terminal kinase activationby proinflammatory stimuli and growth factor-induced cell migration

Exposure of eukaryotic cells to extracellular stimuli results in activation of mitogen-activated protein kinase (MAPK) cascades composed of MAPKs, MAR K kinases (MAP2Ks), and MARK kinase kinases (MAP3Ks). Mammals possess a lar ge number of MAP3Ks, many of which can activate the c-Jun N-terminal kinase (JNK) MARK cascade when overexpressed, but whose biological function is po orly understood. We examined the function of the MAP3K MEK kinase 1 (MEKK1) in proinflammatory signaling. Using MEKK1-deficient embryonic stem cells p repared by gene targeting, we find that, in addition to its function in JNK activation by growth factors, MEKK1 is required for JNK activation by dive rse proinflammatory stimuli, including tumor necrosis factor cu, IL-l, doub le-stranded RNA, and lipopolysaccharide. MEKK1 is also essential for induct ion of embryonic stem cell migration by serum factors, but is not required for activation of other MAPKs or the I kappa B kinase signaling cascade.