MLK4β functions as a negative regulator of MAPK signaling and cell invasion

Saab, Widian F. Abi; Brown, Max; Chadee, Deborah N.

doi:10.1038/oncsis.2012.6

Cited by 15 publications

(15 citation statements)

References 26 publications

(46 reference statements)

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“…These results indicate that MLK4 has a suppressive effect on JNK and p38 activation in response to thermostress, and ERK, JNK and p38 activation in response to osmotic stress. Notably, phospho-MLK3 levels were increased in MLK4 siRNA knockdown cells that were untreated or exposed to osmotic or heat stresses, which supports previous findings that MLK4β suppresses MLK3 activation [4]. Interestingly, we observed that MLK3 is required for sorbitol, but not heat-induced activation of ERK, JNK and p-38 (Supplemental Figure 2).…”

Section: Resultssupporting

confidence: 90%

“…1A and B). As MLK4β suppresses MAPK signalling in certain cellular contexts, we postulated that the reduction in MLK4β might contribute to elevation inMAPK signalling in response to these stress stimuli [4]. To examine the role of MLK4β in ERK, p38 and JNK activation in response to short-term exposure to heat and osmotic stresses, RNA interference-mediated knockdown of MLK4β was performed in SKOV3 cells that were subsequently exposed to heat or treated with sorbitol for 2 h or 4 h. Cell extracts were immunoblotted for activated forms of MLK3, ERK, JNK and p38.…”

Section: Resultsmentioning

confidence: 99%

“…MLK3, the most extensively studied member of the MLK subfamily, has critical functions in migration and invasion in breast, gastric, and ovarian cancer cells; and MLK3 regulates neuronal cell apoptosis [9–12]. MLK3 has more than 70% sequence identity to the MLK4 catalytic domain; however, recent studies indicate non-redundant functions of these enzymes in normal and neoplastic cells [3, 4, 13, 14]. …”

Section: Introductionmentioning

confidence: 99%

“…MLK4β negatively regulates basal as well as stimulus-induced MAPK signalling, ovarian cancer cell invasion, and matrix metalloproteinase 9 activity [3, 4]. In response to TNFα and osmotic stress, MLK4β down-regulates p38 signalling, which was proposed to be mediated through binding and inhibition of MLK3 kinase activity [4]. MLK4 interacts with toll-like receptor 4 and suppresses lipopolysaccharide-induced c-Jun N-terminal kinase (JNK) and extracellular stimulus-regulated kinase (ERK) signalling [3].…”

Section: Introductionmentioning

confidence: 99%

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Osmotic and heat stress-dependent regulation of MLK4β and MLK3 by the CHIP E3 ligase in ovarian cancer cells

Blessing

Kasturirangan

Zink

et al. 2017

Cellular Signalling

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Mixed Lineage Kinase 3 (MLK3), a member of the MLK subfamily of protein kinases, is a mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) that activates MAPK signalling pathways and regulates cellular responses such as proliferation, invasion and apoptosis. MLK4β, another member of the MLK subfamily, is less extensively studied, and the regulation of MLK4β by stress stimuli is not known. In this study, the regulation of MLK4β and MLK3 by osmotic stress, thermostress and heat shock protein 90 (Hsp90) inhibition was investigated in ovarian cancer cells. MLK3 and MLK4β protein levels declined under conditions of prolonged osmotic stress, heat stress or exposure to the Hsp90 inhibitor geldanamycin (GA); and MLK3 protein declined faster than MLK4β.–Similar to MLK3, the reduction in MLK4β protein in cells exposed to heat or osmotic stresses occurred via a mechanism that involves the E3 ligase, carboxy-terminus of Hsc70-interacting protein (CHIP). Both heat shock protein 70 (Hsp70) and CHIP overexpression led to polyubiquitination and a decrease in endogenous MLK4β protein, and MLK4β was ubiquitinated by CHIP in vitro. In untreated cells and cells exposed to osmotic and heat stresses for short time periods, small interfering RNA (siRNA) knockdown of MLK4β elevated the levels of activated MLK3, c-Jun N-terminal kinase (JNK) and p38 MAPKs. Furthermore, MLK3 binds to MLK4β, and this association is regulated by osmotic stress. These results suggest that in the early response to stressful stimuli, MLK4β-MLK3 binding is important for regulating MLK3 activity and MAPK signalling, and after prolonged periods of stress exposure, MLK4β and MLK3 proteins decline via CHIP-dependent degradation. These findings provide insight into how heat and osmotic stresses regulate MLK4β and MLK3, and reveal an important function for MLK4β in modulating MLK3 activity in stress responses.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Osmotic and heat stress-dependent regulation of MLK4β and MLK3 by the CHIP E3 ligase in ovarian cancer cells

Blessing

Kasturirangan

Zink

et al. 2017

Cellular Signalling

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“…The poorly characterized serine/threonine kinase MLK4 is abundantly expressed in various cancers (Abi Saab et al, 2012; Martini et al, 2013). Therefore, our data is applicable to other cancer types beyond GBM and provides a rationale for the therapeutic targeting of MLK4 and/or the MLK4/ NF-κB complex in a broader context.…”

Section: Discussionmentioning

confidence: 99%

Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner

et al. 2016

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SUMMARY Activation of NF-kB induces mesenchymal (MES) trans-differentiation and radio-resistance in glioma stem cells (GSCs), but molecular mechanisms for NF-kB activation in GSCs are currently unknown. Here we report that mixed lineage kinase 4 (MLK4) is overexpressed in MES but not proneural (PN) GSCs. Silencing MLK4 suppresses self-renewal, motility, tumorigenesis, and radio-resistance of MES GSCs via a loss of the MES signature. MLK4 binds and phosphorylates the NF-κB regulator IKKα, leading to activation of NF-κB signaling in GSCs. MLK4 expression is inversely correlated with patient prognosis in MES, but not PN high-grade gliomas. Collectively, our results uncover MLK4 as an upstream regulator of NF-kB signaling and a potential molecular target for the MES subtype of GBMs.

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Thymoquinone inhibits proliferation and invasion of human nonsmall-cell lung cancer cells via ERK pathway

Yang

Kuang

et al. 2014

Tumor Biol.

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Thymoquinone (TQ) is the primary bioactive component of Nigella sativa Linn seed oil and used as anti-inflammatory, anti-oxidant, and anti-neoplastic agent. Previous studies have shown that TQ exhibits inhibitory effects on multiple cancers. However, the detailed antineoplastic effects and its molecular mechanisms of TQ on lung cancer are not entirely elucidated yet. In the present study, we aimed to investigate the effects of TQ on cell proliferation, migration, and invasion as well as its underlying anti-metastatic mechanisms in A549 cells. Lung cancer cell line A549 cells were treated with different concentration of TQ for different period of time, and the growth-inhibitory effects of TQ was measured by MTT and cell count assays; cell cycle was determined by flow cytometry; wound healing and transwell assays were used to assess the cell migration and invasion activities; Western blot and real-time quantitative RT-PCR were used to determine the expression of proliferation and invasion associated genes as well as MAPKs pathway molecules; gelatinase activity was estimated using gelatin zymography assay. The results show that TQ played a role in inhibiting the proliferation, migration, and invasion of A549 lung cancer cells, it also inhibited the expression level of PCNA, cyclin D1, MMP2, and MMP9 mRNA and protein in a dose- and time-dependent manner especially at 10, 20, 40 μmol/L concentrations. The cell cycle inhibitor P16 expression and the gelatinase activities of MMP2 and MMP9 were also inhibited by TQ dramatically. TQ reduced phosphorylation of ERK1/2; however, the proliferation and invasion inhibitory effects of TQ on A549 cells were neutralized by ERK1/2 inhibitor PD98059. In conclusion, our study confirmed that TQ could inhibit A549 cell proliferation, migration, and invasion through ERK1/2 pathway, as proposed the therapeutic potential of TQ as an anti-metastatic agent in human lung cancer treatment.

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MLK4β functions as a negative regulator of MAPK signaling and cell invasion

Cited by 15 publications

References 26 publications

Osmotic and heat stress-dependent regulation of MLK4β and MLK3 by the CHIP E3 ligase in ovarian cancer cells

Osmotic and heat stress-dependent regulation of MLK4β and MLK3 by the CHIP E3 ligase in ovarian cancer cells

Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner

Thymoquinone inhibits proliferation and invasion of human nonsmall-cell lung cancer cells via ERK pathway

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