The stimulation of Toll-like receptors (TLRs) on macrophages triggers production of proinflammatory cytokines such as tumor-necrosis factor-α (TNF-α). The TNF production is mediated by a series of signaling events and subsequent transcriptional and post-transcriptional activation of the TNF gene. Termination of TLR-mediated cellular signaling is also important for a proper immunoresponse, since sustained cytokine expression can result in immune disorders. Here we identified that mixed-lineage kinase (MLK) 4 is a TLR4-interacting protein. Unlike previously characterized MLK group members, MLK4 cannot act as a mitogen-activated protein kinase kinase kinase (MAP3K) to mediate c-Jun N-terminal kinase (JNK), p38 or extracellular signal-regulated kinase (ERK) activation. Rather, MLK4 appears to be able to inhibit lipopolysaccharide (LPS)-induced activation of the JNK or ERK pathways, but does not have effect on LPS-induced p38 or NF-κB activation. The LPS-induced TNF production in MLK4 knockdown and overexpression cells were also increased and reduced, respectively. These data demonstrate that MLK4 is a negative regulator of TLR4 signaling.
Catalysis of the phosphorylation and activation of a MAP kinase kinase; each MAP kinase kinase can be phosphorylated by any of several MAP kinase kinase kinases.
Protein which catalyzes the phosphorylation of serine or threonine residues on target proteins by using ATP as phosphate donor. Such phosphorylation may cause changes in the function of the target protein. Protein kinases share a conserved catalytic core common to both serine/ threonine and tyrosine protein kinases.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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