Dual-specificity phosphatases regulate mitogen-activated protein kinase signaling in adipocytes in response to inflammatory stress

Ferguson, Bradley S.; Nam, Heesun; Morrison, Ron F.

doi:10.1016/j.cellsig.2018.10.011

Cited by 18 publications

(14 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DUSP2 also mediates the dephosphorylation of JNK, while DUSP4 and DUSP16 can promote the phosphorylation of ERK1/2 [39]. Similarly, the absence of DUSP8 will increase the activation of ERK1/2 [40,41]. Figure 5 shows that the LPS-induced decline of DUSP8 was significantly inhibited by EP.…”

Section: Discussionmentioning

confidence: 99%

Ethyl pyruvate inhibits LPS induced IPEC-J2 inflammation and apoptosis through p38 and ERK1/2 pathways

Dong

Xue

et al. 2019

Cell Cycle

View full text Add to dashboard Cite

The endotoxin of Gram-negative bacteria threatens the intestinal health of livestock. Ethyl pyruvate (EP) has been shown to regulate intestinal immunity and protect against cell and tissue damage. In this study, it was first verified that EP could reduce the secretion of IL-8, TNF-α, IL-6 and IL-1β in LPS-induced IPEC-J2 cells. Then, we used RNA sequencing (RNA-seq) to analyze the differentially expressed genes (DEGs) of inflammatory factors induced by LPS in IPEC-J2 cells. It was found that LPS induced the upregulation of 377 genes and the downregulation of 477 genes compared to Vehicle; LPS+EP induced the upregulation of 258 genes and the downregulation of 240 genes compared to Vehicle; and LPS+EP induced the upregulation of 373 genes and the downregulation of 188 genes compared to LPS (fold change > 1.5 and FDR < 0.01). Their enrichment pathways included the MAPK signaling pathway, PI3K-Akt signaling pathway, Tolllike receptor signaling pathway, and other pathways. Furthermore, the mRNA level of cytokines associated with inflammation and apoptosis enriched in the MAPK pathway was verified by qRT-PCR. Western blots and immunofluorescence revealed that EP significantly inhibited phosphorylated p38 and phosphorylated-ERK1/2 protein expression levels (P < 0.05). The apoptosis due to LPS reduced by EP was significantly inhibited, as shown by Annexin V-FITC/PI staining. According to the results, EP inhibited the expression of IL-8, TNF-α, IL-6 and IL-1β as well as apoptosis by inhibiting the phosphorylation of p38 and ERK1/2 in LPS-induced IPEC-J2 cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Ethyl pyruvate inhibits LPS induced IPEC-J2 inflammation and apoptosis through p38 and ERK1/2 pathways

Dong

Xue

et al. 2019

Cell Cycle

View full text Add to dashboard Cite

show abstract

“…Interestingly, unlike the other MAPKs, p38 can also be activated via MKK-independent pathways, either by ZAP/LCK-mediated Tyr phosphorylation [11] or by interaction with TAB1 [12]. The downregulation/inactivation of the p38 cascade is regulated by various phosphatases, among them are several dual specificity phosphatases termed MAPK phosphatases (MKPs) that operate directly on the MAPKs [13]. As in all MAPK cascades, p38 transmits signals initiated by various agents, including cytokines and environmental queues, but it is known to operate mainly as a mediator of stress responses.…”

Section: Introductionmentioning

confidence: 99%

“…Being responsible for the various distinct and even opposing fundamental cellular processes, the p38 cascade needs to be tightly regulated. Indeed, several regulatory mechanisms that determine the specificity of the cascade have been identified, including the duration and strength of the signals [13,14], which are controlled mainly by dual specificity phosphatases [15,16], scaffold proteins [17], and dynamic subcellular localization of the cascade's components [18]. Importantly, the central roles of the cascade suggest that its dysregulation may cause various diseases.…”

Section: Introductionmentioning

confidence: 99%

Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation

Maik-Rachline

Lifshits

Seger

2020

IJMS

View full text Add to dashboard Cite

The p38 mitogen-activated protein kinase (p38MAPK, termed here p38) cascade is a central signaling pathway that transmits stress and other signals to various intracellular targets in the cytoplasm and nucleus. More than 150 substrates of p38α/β have been identified, and this number is likely to increase. The phosphorylation of these substrates initiates or regulates a large number of cellular processes including transcription, translation, RNA processing and cell cycle progression, as well as degradation and the nuclear translocation of various proteins. Being such a central signaling cascade, its dysregulation is associated with many pathologies, particularly inflammation and cancer. One of the hallmarks of p38α/β signaling is its stimulated nuclear translocation, which occurs shortly after extracellular stimulation. Although p38α/β do not contain nuclear localization or nuclear export signals, they rapidly and robustly translocate to the nucleus, and they are exported back to the cytoplasm within minutes to hours. Here, we describe the physiological and pathological roles of p38α/β phosphorylation, concentrating mainly on the ill-reviewed regulation of p38α/β substrate degradation and nuclear translocation. In addition, we provide information on the p38α/β ′s substrates, concentrating mainly on the nuclear targets and their role in p38α/b functions. Finally, we also provide information on the mechanisms of nuclear p38α/b translocation and its use as a therapeutic target for p38α/β-dependent diseases.

show abstract

“…ERK, JNK and p38-dephosphorylating Dusp1 were reported to modulate glucose homeostasis. Less is known about MKPs specific for JNK and/or p38, namely Dusp8, Dusp10 and Dusp16 given their expression in both the cytoplasm and cell nucleus and their relatively selective substrate specificity (4,6,7). Dusp8 appears to be of particular importance for the control of glucose homeostasis based upon recent genome-wide association studies (GWAS) that linked minor allele carriers of the SNP rs2334499 on chromosome 11p15, a region containing DUSP8 among a number of other genes, with a moderately increased risk for T2D risk (8,9).…”

Section: Introductionmentioning

confidence: 99%

Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity

Schriever¹,

Kabra²,

Pfuhlmann³

et al. 2020

Journal of Clinical Investigation

View full text Add to dashboard Cite

Recent genome-wide association studies (GWAS) identified DUSP8, a dual-specificity phosphatase targeting MAP kinases, as type 2 diabetes (T2D) risk gene. Here, we unravel Dusp8 as gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male but not female Dusp8 loss-of-function mice, either with global or CRH neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal (HPA) axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8 KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity and systemic glucose tolerance was consistent with fMRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as novel hypothalamic factor that plays a functional role in the etiology of T2D.

show abstract

Dual-specificity phosphatases regulate mitogen-activated protein kinase signaling in adipocytes in response to inflammatory stress

Cited by 18 publications

References 61 publications

Ethyl pyruvate inhibits LPS induced IPEC-J2 inflammation and apoptosis through p38 and ERK1/2 pathways

Ethyl pyruvate inhibits LPS induced IPEC-J2 inflammation and apoptosis through p38 and ERK1/2 pathways

Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation

Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity

Contact Info

Product

Resources

About