MAP kinase kinase kinase (MEKK3 or MAP3K3) is a serine/threonine protein kinase that activates SAPK and ERK via phosphorylation and activation of their respective MAP kinase kinases, SEK and MEK1/2. MEKK3 also stimulates MEK5 via activation of ERK5/BMK1, which is at least partly regulated by a direct interaction between MEK5 and MEKK3 via p67phox-Bem1p (PB1) protein-protein interaction domains found in both proteins. MEKK3 modulates NF-κB activation in response to a variety of agonists including TNFα, LPS, IL-1 and LPA. Despite reports showing that phosphorylation of MEKK3 at Ser526 within the activation loop is necessary for kinase activation, at least one study suggests that dual phosphorylation at Thr516 and Ser520 is required for LPA-stimulated IKKβ/NF-κB activation. Phosphorylation at Thr294 appears to negatively regulate MEKK3 by promoting 14-3-3β binding and inhibition of the kinase activity.
