Mixed lineage kinases (MLKs): a role in dendritic cells, inflammation and immunity?

Abstract

Summary This review summarizes current knowledge about the mixed lineage kinases (MLKs) and explores their potential role in inflammation and immunity. MLKs were identified initially as signalling molecules in the nervous system. They were also shown to play a role in the cell cycle. Further studies documented three groups of MLKs, and showed that they may be activated via the c‐Jun NH2 terminal kinase (JNK) pathway, and by Rho GTPases. The biochemistry of the MLKs has been investigated in considerable detail. Homodimerization and heterodimerization can occur, and both autophosphorylation and autoinhibition are seen. The interaction between MLKs and JNK interacting protein (JIP) scaffolds, and the resultant effects on mitogen activated protein kinases, have been identified. Clearly, there is some redundancy within the MLK pathway(s), since mice which lack the MLK3 molecule are not abnormal. However, using a combination of biochemical analysis and pharmacological inhibitors, several recent studies in vitro have suggested that MLKs are not only expressed in cells of the immune system (as well as in the nervous system), but also may be implicated selectively in the signalling pathway that follows on toll‐like receptor ligation in innate sentinel cells, such as the dendritic cell.

Mixed Lineage Kinase Phosphorylates Transcription Factor E47 and Inhibits TrkB Expression to Link Neuronal Death and Survival Pathways

“…1B). Because MLKs undergo autophosphorylation to become fully active (17,19), this result suggests that autophosphorylation might also be important to acquire a competent conformation to interact with E47. NeuroD overexpression did not affect co-immunoprecipitation of E47 and FLAG-MLK2, suggesting that NeuroD would not mediate their interaction (25).…”

“…3A). On the other hand, although MLKs show similarities to serine-threonine and tyrosine kinases, so far they have been shown to phosphorylate only serine and threonine residues in downstream kinases (17,19). Thus, we searched for serine and threonine residues in E47 near the putative MLK docking site that were conserved from fish to human.…”

“…The name "mixed lineage kinases" derives from the fact that of the 11 conserved subdomains found in all protein kinases, domains 1-8 of the MLK proteins resemble serine/threonine kinases, whereas regions 9 -11 share sequence similarity with those of tyrosine kinases, such as the fibroblast growth factor receptor and Src (17)(18)(19). Eight mammalian MLKs have been identified and categorized into three subfamilies on the basis of domain organization and sequence similarity: MLKs, dual leucine zipper-bearing kinases (DLKs), and zipper sterile ␣-motif kinases (ZAKs).…”

Adjunctive and long-acting nanoformulated antiretroviral therapies for HIV-associated neurocognitive disorders

“…1), and also regulate the other two major MAPK pathways, p38 and extracellular signal-regulated kinase (ERK) [9–11]. MLK3 (aka MAP3K11) is the most widely expressed MLK family member [9–11] and is known to be expressed in neurons [12], dendritic cells [13, 14], and many other cell types. At the cellular level, MLK3 is activated by cellular/metabolic stress, including reactive oxygen species, ceramide and TNF-α [15, 16].…”

Hepatitis B Virus X Protein Modulates Apoptosis in NRK-52E Cells and Activates Fas/FasL Through the MLK3-MKK7-JNK3 Signaling Pathway

“…An important component of this pathway is the mixed-lineage kinase (MLK) family of kinases, which activate signal transduction pathways that induce neuronal cell death [15]. This family has three subgroups: MLKs (MLK1-4), dual leucine zipper-bearing kinases (DLKs), and Zipper Sterile-a-Motif Kinases (ZAKs) [16][17][18]. Studies of ischemic brain injury provide evidence that the ischemia-stimulating factor can activate the MLK3-MKK7-JNKs signaling module to activate the death receptor pathway, leading to apoptosis of neural cells [19,20].…”