Protein Tyrosine Phosphatase N2 Is a Positive Regulator of Lipopolysaccharide Signaling in Raw264.7 Cell through Derepression of Src Tyrosine Kinase

Thi, Huyen Trang Ha; Choi, Seowon; Kim, Youngmi; Kim, Hye-Youn

doi:10.1371/journal.pone.0162724

Cited by 5 publications

(6 citation statements)

References 27 publications

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“…Src is activated by upstream receptor tyrosine kinases such as Met or EGFR, but it is also affected by intracellular protein tyrosine phosphatases e.g. protein tyrosine phosphatase non-receptor type 1 (PTPN1) and 2 (PTPN2) (19,20). PTPN1 expression status appears to have no or limited impact in HER2-positive breast cancer or breast cancer patients undergoing neoadjuvant chemotherapy, whilst PTPN2 has been reported to be frequently lost in breast cancer, correlating with poor outcome (21–24).…”

Section: Introductionmentioning

confidence: 99%

ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2‑positive metastatic breast cancer treated with trastuzumab

et al. 2019

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Trastuzumab has markedly improved the treatment and long-term prognosis of patients with HER2-positive breast cancer. A frequent clinical challenge in patients with relapsing and/or metastatic disease is de novo or acquired trastuzumab resistance, and to date no predictive biomarkers for palliative trastuzumab have been established. In the present study, the prognostic values of factors involved in the HER2-associated PI3K/Akt signalling pathway were explored. The first 46 consecutive patients treated at the Department of Oncology, Linköping University Hospital between 2000 and 2007 with trastuzumab for HER2-positive metastatic breast cancer were retrospectively included. The gene copy number variation and protein expression of several components of the PI3K/Akt pathway were assessed in the tumour tissue and biopsy samples using droplet digital polymerase chain reaction and immunohistochemistry. Patients with tumours displaying a high-grade ERBB2 (HER2) amplification level of ≥6 copies had a significantly improved overall survival hazard ratio [(HR)=0.4; 95%, confidence interval (CI): 0.2–0.9] and progression-free survival (HR=0.3; 95% CI: 0.1–0.7) compared with patients with tumours harbouring fewer ERBB2 copies. High-grade ERBB2 amplification was significantly associated with the development of central nervous system metastases during palliative treatment. Copy gain (≥3 copies) of the gene encoding the tyrosine phosphatase PTPN2 was associated with a shorter overall survival (HR=2.0; 95% CI: 1.0–4.0) and shorter progression-free survival (HR=2.1; 95% CI: 1.0–4.1). In conclusion, high ERBB2 amplification level is a potential positive prognostic factor in trastuzumab-treated HER2-positive metastatic breast cancer, whereas PTPN2 gain is a potential negative prognostic factor. Further studies are warranted on the role of PTPN2 in HER2 signalling.

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Section: Introductionmentioning

confidence: 99%

ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2‑positive metastatic breast cancer treated with trastuzumab

et al. 2019

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“…These include but are not limited to upstream regulators associated with neuronal activity and neurotransmission [NEUROD1 (Z-score 2.373), norepinephrine (Z-score 2.946), FOS (Z-score -2.026), FOSB (Z-score -2.2), and SLC16A2 (Z-score -2.074)], microglia-enriched transcription factors [SAL4 (Z-score 3.889), RARG (Z-score 2.186) and TEAD4 (Z-score -2.005)] and inflammatory signaling [CD247 (Z-score 2.236), IL9 (Z-score 2.229), TLR9 (Z-score 2.155), AMPK (Z-score 2.08), FHL2 (Z-score -2.804), IL3 (Z-score -2.428), CD40 (Z-score -2.382), HMGXB4 (Z-score -2.236), PTPN2 (Z-score -2.219), CD40LG (Z-score -2.21), CCL5 (Z-score -2.179), LTA (TNFβ) (Z-score -2.138), TIMP1 (Z-score -2.111), and NFKB1 (Z-score -2.015)]. Some notable effects were the activation of norepinephrine, the microglia-enriched transcription factors RARG and TEAD4 (Ayata, Badimon et al 2018) and the inhibition of the negative regulator of Wnt signaling, HMGXB4 (He, Dong et al 2021), as well as of NFKB1 and the negative regulators of NF-kB and inflammasome activation, FHL2 and PTPN2 (Ha Thi, Choi et al 2016, Dahan, Levillayer et al 2017). These experiments demonstrated a significant interaction between dopamine and the regulation of inflammation in human microglia and suggest further research in this area is needed to better define these effects.…”

Section: Resultsmentioning

confidence: 99%

Dopamine-driven Increase in IL-1β in Myeloid Cells is Mediated by Differential Dopamine Receptor Expression and Exacerbated by HIV

Matt,

Nolan,

Manikandan

et al. 2024

Preprint

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The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-κB activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1β in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1β in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1β, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1β. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1β gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1β signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1β in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1β, will be critical to effectively tailor medication regimens.

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“… 33 The activation of the MAPK and NF-κB signalling pathways induced by LPS was reduced following PTPN2 knockdown and PTPN2 acted as a positive regulator of LPS-induced inflammation. 34 In contrast, loss of PTPN2 was reported to promote the phosphorylation of p38 MAPK and contribute to NF-κB overexpression. 14 , 35 The regulatory mechanism of PTPN2 in inflammatory events are controversial.…”

Section: Discussionmentioning

confidence: 99%

Wedelolactone improves the renal injury induced by lipopolysaccharide in HK-2 cells by upregulation of protein tyrosine phosphatase non-receptor type 2

et al. 2021

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Objective To explore the effects of wedelolactone (WEL) on sepsis-induced renal injury in the human renal proximal tubular epithelial cell line HK-2. Methods HK-2 cells were stimulated by 1 µg/ml lipopolysaccharide (LPS) to trigger renal injury in vitro. HK-2 cells were pretreated with or without WEL (0.1, 1 and 10 µM) before LPS stimulation. Protein and mRNA analyses were performed using enzyme-linked immunosorbent assays, Western blot analysis and quantitative reverse transcription–polymerase chain reaction. The MTT assay and flow cytometry were used to measure cell viability and the rate of cell apoptosis. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) knockdown was induced by the transection of HK-2 cells with short hairpin RNA. Results Cell viability was significantly increased in a dose-dependent manner by WEL in LPS-induced HK-2 cells. WEL also decreased the levels of four inflammatory cytokines and cell apoptosis in LPS-induced HK-2 cells. The level of PTPN2 was increased after WEL treatment. PTPN2 knockdown partly abolished the inhibitory effects of WEL on cell apoptosis, the levels of inflammatory cytokines and on p38 mitogen-activated protein kinase/nuclear factor-kappaB signalling in LPS-induced HK-2 cells. Conclusion WEL improved renal injury by suppressing inflammation and cell apoptosis through upregulating PTPN2 in HK-2 cells. PTPN2 might be used as a potential therapeutic target for LPS-induced sepsis.

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Protein Tyrosine Phosphatase N2 Is a Positive Regulator of Lipopolysaccharide Signaling in Raw264.7 Cell through Derepression of Src Tyrosine Kinase

Cited by 5 publications

References 27 publications

ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2‑positive metastatic breast cancer treated with trastuzumab

ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2‑positive metastatic breast cancer treated with trastuzumab

Dopamine-driven Increase in IL-1β in Myeloid Cells is Mediated by Differential Dopamine Receptor Expression and Exacerbated by HIV

Wedelolactone improves the renal injury induced by lipopolysaccharide in HK-2 cells by upregulation of protein tyrosine phosphatase non-receptor type 2

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