Abstract
Mixed lineage kinase (MLK) 4, or MLK4, is a member of the MLK family of mitogen-activated protein kinase kinase kinases (MAP3Ks). Typically, MAP3Ks function to activate the mitogen-activated protein kinase (MAPK)-signaling pathways and regulate different cellular responses. However, here we report that MLK4β, unlike the other MLKs, negatively regulates the activities of the MAPKs, p38, c-Jun N-terminal kinase and extracellular signal-regulated kinase, and the MAP2Ks, MEK3 and 6. Our results show that MLK4β inhibits sorbitol- and tumor necrosis factor-induced activation of p38. Furthermore, MLK4β interacts with another MLK family member, MLK3, in HCT116 cells. Exogenous expression of MLK4β inhibits activation of MLK3 and also blocks matrix metalloproteinase-9 gelatinase activity and invasion in SKOV3 ovarian cancer cells. Collectively, our data establish MLK4β as a novel suppressor of MLK3 activation, MAPK signaling and cell invasion.
Highlights
Mitogen-activated protein kinases (MAPKs) are serine/threonine kinases that regulate a variety of cellular processes including proliferation, inflammation, invasion and apoptosis.[1,2] The mammalian extracellular signal-regulated kinases (ERKs), c-JunN-terminal kinase (JNK) and p38 kinase are three major mitogen-activated protein kinase (MAPK) families that are activated by a wide range of stimuli.[3]
A further increase in the level of p-p38 was observed in the MLK4-knockdown cells as compared with cells treated with the nonspecific small interfering RNA (siRNA) oligo (Figure 1a, right panel)
Overexpressing MLK4b almost completely abolished the level of pp[38] that was observed in untreated and sorbitol-treated cells transfected with an empty vector (Figure 1b). p38 signaling is activated by cytokines.[2,6]
Summary
Mitogen-activated protein kinases (MAPKs) are serine/threonine kinases that regulate a variety of cellular processes including proliferation, inflammation, invasion and apoptosis.[1,2] The mammalian extracellular signal-regulated kinases (ERKs), c-JunN-terminal kinase (JNK) and p38 kinase are three major MAPK families that are activated by a wide range of stimuli.[3]. MAPKs are phosphorylated and activated by the mitogen-activated protein kinase kinases (MAP2Ks or MEKs), which are in turn phosphorylated and activated by the mitogenactivated protein kinase kinase kinases (MAP3Ks).[2,7,8]
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