Suppression of GSK3β by ERK mediates lipopolysaccharide induced cell migration in macrophage through β-catenin signaling

Gong, Kai; Zhou, Fangfang; Huang, Huizhe; Gong, Yandao; Zhang, Long

doi:10.1007/s13238-012-2058-x

Cited by 26 publications

(25 citation statements)

References 29 publications

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“…The non‐canonical Wnt5a‐induced immune‐activating signaling can be triggered by mycobacteria or isolated TLR ligands and results in increased expression of pro‐inflammatory cytokines . On the other hand, canonical Wnt3a‐mediated effects on Mϕ have been shown to down‐regulate glycogen synthase kinase‐3β, which led to decreased NF‐κB signaling and reduced pro‐inflammatory cytokine production . Our findings of canonical Wnt/β‐catenin signaling activation in the T‐cell suppressive M(IL‐13,‐10) subset fits with the immunosuppressive role of this pathway.…”

Section: Discussionsupporting

confidence: 72%

“…Notably, our study revealed an up‐regulation of the canonical Wnt/β‐catenin signaling pathway in M(IL‐13,‐10). This pathway, which is best known for its role in regulating embryonic development, has also been described as being crucially involved in immune modulation and Mϕ function . Although Mϕ are known as a major source of different Wnt molecules, inducing tumor cell proliferation in a paracrine fashion, the role of Mϕ intrinsic Wnt/β‐catenin signaling is less clear .…”

Section: Discussionmentioning

confidence: 99%

“…This pathway, which is best known for its role in regulating embryonic development, has also been described as being crucially involved in immune modulation and M function. [46][47][48] Although M are known as a major source of different Wnt molecules, inducing tumor cell proliferation in a paracrine fashion, the role of M intrinsic Wnt/ -catenin signaling is less clear. [49][50][51][52] Nevertheless, an involvement of this pathway in inflammatory and suppressive M responses was described.…”

Section: Discussionmentioning

confidence: 99%

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Effects of IL-10 and Th2 cytokines on human Mφ phenotype and response to CSF1R inhibitor

Pradel

Franke²

2018

Journal of Leukocyte Biology

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Tumor-associated Mφs display a plastic phenotype that is regulated by the local tumor milieu. Gene expression analysis and functional characterization of Mφs exposed in vitro to individual cytokines aids to delineate the cross-talk between defined cytokines shaping the complex Mφ phenotype. Human monocyte-derived Mφs can be differentiated in vitro with the T helper cell type 2 response cytokines IL-4 and IL-13 or the immunosuppressive IL-10. Notably, only the latter subset undergoes apoptosis when treated with the CSF 1 receptor (CSF1R) blocking antibody emactuzumab. However, under physiologic conditions, the Mφ phenotype is regulated by cytokine combination. Hence, in this study, we characterized the plasticity of IL-4 or IL-13-differentiated Mφs upon exposure to the immunosuppressive IL-10. Although IL-4-differentiated Mφs sustained their molecular phenotype in the presence of IL-10, IL-13-differentiated Mφs were skewed towards the IL-10 phenotype. Gene expression profiling revealed unique IL-4+IL-10 and IL-13+IL-10 Mφ signatures associated with up-regulation of canonical NF-κB or Wnt/β-catenin signaling pathways, respectively. Although IL-10 was able to alter the surface marker and gene expression profile of IL-13-differentiated Mφs, addition of IL-10 did not restore emactuzumab susceptibility. Combining NF-κB and Wnt/β-catenin signaling inhibitors with emactuzumab had no effect on viability. On average 3-5% of cancer patients overexpressed IL-4, IL-13, or IL-10 mRNA in silico. Although a small patient subset overexpressed IL-10+IL-13, IL-4+IL-10 lacked co-expression. In vitro characterization of CSF1R inhibitor-refractory Mφ phenotypes can support novel pharmacological approaches to specifically target these cells.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of IL-10 and Th2 cytokines on human Mφ phenotype and response to CSF1R inhibitor

Pradel

Franke²

2018

Journal of Leukocyte Biology

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“…Interestingly, we observed that suppression of ERK1/2 activation by U1206 also attenuated GSK3β phosphorylation, which was accompanied by p21 destabilization, suggesting that ERK1/2 activation is the upstream event and is required for GSK phosphorylation. Gong et al also showed that ERK1/2 activation could induce GSK3 suppression by coupling AKT‐dependent phosphorylation . This is the first report, to our knowledge, that activated ERK1/2 repressed HCC growth by stabilizing p21 Waf/Cip1 .…”

Section: Resultsmentioning

confidence: 57%

Hippocalcin‐like 1 suppresses hepatocellular carcinoma progression by promoting p21Waf/Cip1 stabilization by activating the ERK1/2‐MAPK pathway

et al. 2016

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. However, the underlying mechanism during hepatocarcinogenesis remains unclarified. Stable isotope labeling by amino acids in cell culture (SILAC) is a powerful quantitative strategy for proteome-wide discovery of novel biomarkers in cancers. Hippocalcin-like 1 (HPCAL1) is a calcium sensor protein. However, the biological function of HPCAL1 is poorly understood in cancers, including HCC. Herein, HPCAL1 was identified by SILAC as a novel hepatocarcinogenesis suppressor down-regulated in HCC cell lines and tissues. Importantly, lost expression of HPCAL1 was associated with worse prognosis of HCC patients. Interestingly, secreted HPCAL1 protein in the plasma dropped dramatically in HCC patients compared with healthy donors. Receiver operating characteristic curve analysis showed that serum HPCAL1 at a concentration of 8.654 ng/mL could better predict HCC. Furthermore, ectopic expression of HPCAL1 suppresses cell proliferation, while depletion of HPCAL1 led to increased cell growth both in vitro and in vivo. Mechanistically, HPCAL1 directly interacted with p21 Waf/Cip1 in the nucleus, which requires the EF-hand 4 motif of HPCAL1 and the Cy1 domain of p21. This interaction stabilized p21 Waf/Cip1 in an extracellular signal-regulated kinase 1/2-mitogen-activated protein kinase-dependent manner, which subsequently prevented p21 Waf/Cip1 proteasomal degradation by disrupting SCF Skp2 and CRL4 Cdt2 E3 ligase complexes, resulting in increased protein stability and inhibitory effect of p21 Waf/Cip1 . Notably, the tumor suppressive function of HPCAL1 was dependent on p21 in vitro and in vivo. Consistent with this observation, expression of HPCAL1 and p21 Waf/Cip1 was positively correlated in HCC tissues. Conclusion: These findings highlight a novel tumor suppressor upstream of p21 Waf/Cip1 in attenuating cell cycle progression and provide a promising diagnostic and prognostic factor, as well as a potential therapeutic target for HCC. (HEPATOLOGY 2016;63:880-897) H epatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the third leading cause of cancer-related death. (1) In the past decades, despite the availability of improved diagnostic techniques and progress in surgical and nonsurgical therapies, the prognosis of HCC has remained poor due to easy metastasis and high recurrence rates after surgical resection. (2) Hepatocarcinogenesis is characterized in part by deregulated cell cycle progression, which contributes to excessive Abbreviations: CDK, cyclin-dependent kinase; CHX, cycloheximide; co-IP, coimmunoprecipitation; ERK, extracellular signal-regulated kinase; GSK, glycogen synthase kinase; GST, glutathione S-transferase; HCC, hepatocellular carcinoma; HPCAL1, hippocalcin-like 1; IHC, immunohistochemistry; LC-MS/MS, liquid chromatography-tandem mass spectrometry; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; MS, mass spectrometry; qRT-PCR, quantitative reverse-transcription polymerase chain re...

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“…Gong and colleagues reported that ERK could suppress GSK-3β activation, stimulate β-catenin signaling and induce cell migration in lipopolysaccharide-treated macrophages. 56 Additionally, radiation can also lead to the activation of MEK/ERK through the accumulation of reactive oxygen species and the resultant inactivation of GSK-3β, eventually leading to Snail nuclear retention and the promotion of mesenchymal phenotypic changes in lung carcinoma epithelial cells. 57 Although there is no direct evidence that MCP-1 can inactivate GSK-3β via ERK1/2, we hypothesize that MCP-1 can inhibit GSK-3β and activate Snail via the MEK/ERK signaling pathway.…”

Section: Mcp-1-induced Emt Of Mcf-7 Cells S LI Et Almentioning

confidence: 99%

MCP-1-induced ERK/GSK-3β/Snail signaling facilitates the epithelial–mesenchymal transition and promotes the migration of MCF-7 human breast carcinoma cells

Lü

Chen

et al. 2016

Cell Mol Immunol

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Monocyte chemoattractant protein-1 (MCP-1) is a chemotactic cytokine that can bind to its receptor cysteine-cysteine chemokine receptor 2 (CCR2) and plays an important role in breast cancer cell metastasis. However, the molecular mechanisms underlying MCP-1-induced alterations in cellular functions during tumor progression are poorly understood. Here, we showed that MCP-1 stimulated the epithelial-mesenchymal transition (EMT) and induced the tumorigenesis of breast cancer cells by downregulating E-cadherin, upregulating vimentin and fibronectin, activating matrix metallopeptidase-2 (MMP-2), and promoting migration and invasion. Moreover, MCP-1 treatment reduced glycogen synthase kinase-3β (GSK-3β) activity via the MEK/ERK-mediated phosphorylation of serine-9 in MCF-7 cells. The inhibition of MEK/ERK by U0126 attenuated the MCP-1-induced phosphorylation of GSK-3β and decreased the expression of Snail, an EMT-related transcription factor, leading to the inhibition of MCF-7 cell migration and invasion. Inactivation of GSK-3β by LiCl (lithium chloride) treatment notably increased MMP-2 activity, vascular endothelial growth factor expression and EMT of MCF-7 cells. These findings revealed that MCP-1-induced EMT and migration are mediated by the ERK/GSK-3β/Snail pathway, and identified a potential novel target for therapeutic intervention in breast cancer. Cellular & Molecular Immunology

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Suppression of GSK3β by ERK mediates lipopolysaccharide induced cell migration in macrophage through β-catenin signaling

Cited by 26 publications

References 29 publications

Effects of IL-10 and Th2 cytokines on human Mφ phenotype and response to CSF1R inhibitor

Effects of IL-10 and Th2 cytokines on human Mφ phenotype and response to CSF1R inhibitor

Hippocalcin‐like 1 suppresses hepatocellular carcinoma progression by promoting p21Waf/Cip1 stabilization by activating the ERK1/2‐MAPK pathway

MCP-1-induced ERK/GSK-3β/Snail signaling facilitates the epithelial–mesenchymal transition and promotes the migration of MCF-7 human breast carcinoma cells

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