Tyrosine phosphatase SHP2 exacerbates psoriasis‐like skin inflammation in mice via ERK5‐dependent NETosis

Ding, Yan; Zhang, Chenyang; Zhu, Yuyu; Xu, Qiang; Sun, Haiyan; Qu, Jiao; Sun, Yang

doi:10.1002/mco2.120

Cited by 29 publications

(22 citation statements)

References 43 publications

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“… 92 We also recently found that SHP2 in neutrophils aggravated psoriasis by promoting the formation of extracellular neutrophil traps and the subsequent cell death known as NETosis via the ERK5 pathway. 93 SHP2 also mediated keratinocyte proliferation, migration, and differentiation through ERK activation in an IL-22-mediated psoriasis-like model. 94 These results indicated that the function of SHP2 in psoriasis varied depending on the specific immune cell type.…”

Section: The Signaling Pathways Regulated By the Protein Phosphatases...mentioning

confidence: 90%

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Pan

Zhou

Zhang

et al. 2022

Sig Transduct Target Ther

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Inflammation is the common pathological basis of autoimmune diseases, metabolic diseases, malignant tumors, and other major chronic diseases. Inflammation plays an important role in tissue homeostasis. On one hand, inflammation can sense changes in the tissue environment, induce imbalance of tissue homeostasis, and cause tissue damage. On the other hand, inflammation can also initiate tissue damage repair and maintain normal tissue function by resolving injury and restoring homeostasis. These opposing functions emphasize the significance of accurate regulation of inflammatory homeostasis to ameliorate inflammation-related diseases. Potential mechanisms involve protein phosphorylation modifications by kinases and phosphatases, which have a crucial role in inflammatory homeostasis. The mechanisms by which many kinases resolve inflammation have been well reviewed, whereas a systematic summary of the functions of protein phosphatases in regulating inflammatory homeostasis is lacking. The molecular knowledge of protein phosphatases, and especially the unique biochemical traits of each family member, will be of critical importance for developing drugs that target phosphatases. Here, we provide a comprehensive summary of the structure, the “double-edged sword” function, and the extensive signaling pathways of all protein phosphatases in inflammation-related diseases, as well as their potential inhibitors or activators that can be used in therapeutic interventions in preclinical or clinical trials. We provide an integrated perspective on the current understanding of all the protein phosphatases associated with inflammation-related diseases, with the aim of facilitating the development of drugs that target protein phosphatases for the treatment of inflammation-related diseases.

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Section: The Signaling Pathways Regulated By the Protein Phosphatases...mentioning

confidence: 90%

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Pan

Zhou

Zhang

et al. 2022

Sig Transduct Target Ther

Self Cite

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“…Blocking PAD-4 was found to disrupt network formation and therefore increase the risk of bacterial infection in animals [ 26 ]. In addition, the study of Ding et al (2022) showed remarkably ameliorated psoriasis-like symptoms in PAD-4 knockout mice [ 44 ]. Thus, studies using knock-out animals indicated the participation of PAD-4 as a required component for NET-dependent innate antimicrobial immunity [ 26 ] as well as a factor firmly associated with psoriasis development [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the study of Ding et al (2022) showed remarkably ameliorated psoriasis-like symptoms in PAD-4 knockout mice [ 44 ]. Thus, studies using knock-out animals indicated the participation of PAD-4 as a required component for NET-dependent innate antimicrobial immunity [ 26 ] as well as a factor firmly associated with psoriasis development [ 44 ]. Additionally, PAD-4 has been shown to participate in the regulation of proliferation and hematopoiesis [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…Concurrently, we may find the reports providing information about additional mechanisms engaged in the NET generation. Meng (et al 2022) noticed that decreased receptor-interacting serine/threonine-protein kinase 1 (RIPK1) expression in psoriasis neutrophils may enhance traps [ 59 ], whereas Ding et al (2022) indicated that Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) had a high impact on psoriasis severity [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

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Changes in Tumor Necrosis Factor α (TNFα) and Peptidyl Arginine Deiminase 4 (PAD-4) Levels in Serum of General Treated Psoriatic Patients

Czerwińśka

Kasprowicz-Furmańczyk

Placek

et al. 2022

IJERPH

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Psoriasis is an autoimmune disease in which the disturbed dependencies between lymphocytes, dendritic cells, keratinocytes and neutrophils play the most important role. One of them is the overproduction of neutrophil extracellular traps (NETs). The release of NETs can be induced by pathogens, as well as antibodies and immune complexes, cytokines and chemokines, including TNFα. The first step of the NET creation is the activation of peptidyl arginine deiminase 4 (PAD-4). PAD-4 seems to be responsible for citrullination of histones and chromatin decondensation, but the data on PAD-4 in NETs is inconclusive. Thus, the current study aimed to determine PAD-4 and TNFα levels in the serum of psoriatic patients by ELISA and observe the response of these factors to systemic (anti-17a, anti-TNFα and methotrexate) therapies. Increased levels of both PAD-4 and its main stimulus factor TNFα in pre-treatment patients have been reported along with the concentrations of proteins correlated with disease severity (PASI, BSA). Before treatment, the irregularities in the case of anti-nuclear antibodies level (ANA) were also observed. All of the applied therapies led to a decrease in PAD-4 and TNFα levels after 12 weeks. The most significant changes, both in protein concentrations as well as in scale scores, were noted with anti-TNFα therapy (adalimumab and infliximab). This phenomenon may be associated with the inhibition of TNFα production at different stages of psoriasis development, including NET creation. The obtained data suggest the participation of PAD-4 in the activation of neutrophils to produce NETs in psoriasis, which may create opportunities for modern therapies with PAD inhibitors. However, further exploration of gene and protein expression in psoriatic skin is needed.

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“…Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene [ 1 , 2 , 3 , 4 , 5 ]. The SHP2 structure contains two tandem SH2 domains (N-SH2 and C-SH2), a PTP catalytic domain and a C-terminal tail with two tyrosine phosphorylation sites [ 6 , 7 , 8 , 9 ]. SHP2 is located in the cytoplasm, can be recruited by receptor tyrosine kinases (RTKs) to induce cell signaling and participates in the intracellular oncogenic RAS/MAPK cell signaling cascade [ 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged Pyrazoline Derivatives as a Series of Novel SHP2 Inhibitors

Dai

Zhang

Gao

et al. 2022

IJMS

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Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene, which is involved in the RAS/MAPK cell signaling transduction process. SHP2 has been shown to contribute to the progression of various cancers and is emerging as an important target for anti-tumor drug research. However, past efforts to develop SHP2 inhibitors into drugs have been unsuccessful owing to the positively charged nature of the active site pocket tending to bind negatively charged groups that are usually non-drug-like. Here, a series of uncharged pyrazoline derivatives were designed and developed as new SHP2 inhibitors using a structure-based strategy. Compound 4o, which exhibited the strongest SHP2 inhibitory activity, bound directly to the catalytic domain of SHP2 in a competitive manner through multiple hydrogen bonds. Compound 4o affected the RAS/MAPK signaling pathway by inhibiting SHP2, and subsequently induced apoptosis and growth inhibition of HCT116 cells in vitro and in vivo. Notably, the oral administration of compound 4o in large doses showed no obvious toxicity. In summary, our findings provide a basis for the further development of compound 4o as a safe, effective and anti-tumor SHP2 inhibitor.

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Tyrosine phosphatase SHP2 exacerbates psoriasis‐like skin inflammation in mice via ERK5‐dependent NETosis

Cited by 29 publications

References 43 publications

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Changes in Tumor Necrosis Factor α (TNFα) and Peptidyl Arginine Deiminase 4 (PAD-4) Levels in Serum of General Treated Psoriatic Patients

Toward a Treatment of Cancer: Design and In Vitro/In Vivo Evaluation of Uncharged Pyrazoline Derivatives as a Series of Novel SHP2 Inhibitors

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