Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development

Lee, Hyunseung; Kim, Mihwa; Baek, Minwoo; Morales, Liza D.; Jang, Ik Soon; Slaga, Thomas J.; DiGiovanni, John; Kim, Dae Joon

doi:10.1038/srep45077

Cited by 34 publications

(53 citation statements)

References 51 publications

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“…Our findings implied that TC‐PTP promotes apoptosis to eliminate DMBA or TPA damaged keratinocytes via the negative regulation of STAT3 and AKT signaling (Figure ) and thereby, may function as a tumor suppressor by preventing the accumulation of deleterious mutations during tumor initiation and promotion. Consistent with these results, TC‐PTP‐deficient mice presented significantly increased numbers of tumors and a shortened latency of tumorigenesis during two‐stage skin carcinogenesis …”

Section: Role Of Tc‐ptp In Environmental Skin Carcinogenesissupporting

confidence: 79%

“…We demonstrated expression levels of active STAT3 gradually recovered 8 hours after a single treatment of TPA; however, retreatment of cells with TPA for 3 hours decreased phosphorylated STAT3 levels again. This effect was not observed in TC‐PTP knockdown keratinocytes, indicating TC‐PTP was a major modulator in the regulation of STAT3 signaling, especially in response to chemical exposure, such as TPA …”

Section: Role Of Tc‐ptp In Environmental Skin Carcinogenesismentioning

confidence: 93%

“…This effect was not observed in TC-PTP knockdown keratinocytes, indicating TC-PTP was a major modulator in the regulation of STAT3 signaling, especially in response to chemical exposure, such as TPA. 84 To further characterize the role of TC-PTP in our hypothesized skin protective mechanism, we utilized an epidermal-specific TC-…”

Section: Although In Vitro Studies Clearly Have Been Useful In Elucidmentioning

confidence: 99%

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The role of T‐cell protein tyrosine phosphatase in epithelial carcinogenesis

Morales

Archbold

Olivarez

et al. 2019

Molecular Carcinogenesis

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T‐cell protein tyrosine phosphatase (TC‐PTP, encoded by PTPN2) is a nonreceptor PTP that is most highly expressed in hematopoietic tissues. TC‐PTP modulates a variety of physiological functions including cell cycle progression, cell survival and proliferation, and hematopoiesis through tyrosine dephosphorylation of its target substrates, such as EGFR, JAK1, JAK3, STAT1, and STAT3. Studies with whole or tissue‐specific loss of TC‐PTP function transgenic mice have shown that TC‐PTP has crucial roles in the regulation of the immune response, insulin signaling, and oncogenic signaling. More recently, the generation of epidermal‐specific TC‐PTP‐deficient mice for use in multistage skin carcinogenesis bioassays demonstrated that TC‐PTP suppresses skin tumor formation by negatively regulating STAT3 and AKT signaling. Further investigation showed that TC‐PTP also minimizes UVB‐induced epidermal cell damage by promoting apoptosis through the negative regulation of Flk‐1/JNK signaling. These findings provide major evidence for a tumor suppressive function for TC‐PTP against environment‐induced skin cancer. Here, we will discuss TC‐PTP, its substrates, and its functions with an emphasis on its role in skin carcinogenesis.

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Section: Role Of Tc‐ptp In Environmental Skin Carcinogenesissupporting

confidence: 79%

Section: Role Of Tc‐ptp In Environmental Skin Carcinogenesismentioning

confidence: 93%

Section: Although In Vitro Studies Clearly Have Been Useful In Elucidmentioning

confidence: 99%

See 1 more Smart Citation

The role of T‐cell protein tyrosine phosphatase in epithelial carcinogenesis

Morales

Archbold

Olivarez

et al. 2019

Molecular Carcinogenesis

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“…STAT3 signaling pathway is an important downstream mediator of PTPN2 [27] and plays a crucial role in the regulation of T cells polarization [15]. Functional ablation of Stat3 reverses the high Th1/Treg ratio in VAT of obesity mice [15].…”

Section: Discussionmentioning

confidence: 99%

“…However, the role of PTPN2 in adipose tissue T cells polarization remains unknown. In particular, it has been documented that PTPN2 negatively regulates the STAT3 activity either in the cytoplasm, through dephosphorylating protein tyrosine kinase JAK, or in the nucleus, through directly dephosphorylating STAT3 [26, 27]. Functional ablation of Stat3 in T cells reverses the high Th1/Treg ratio in VAT of diet-induced obesity mice [15].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of PTPN2 in Visceral Adipose Tissue Ameliorated Atherosclerosis via T Cells Polarization Shift in Diabetic Apoe-/- Mice

Wang

Zhou

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Dysregulated inflammation in adipose tissue, marked by increased pro-inflammatory T-cell accumulation and reduced regulatory T cells (Treg), contributes to diabetes-associated insulin resistance and atherosclerosis. However, the molecular mechanisms underlying T-cell-mediated inflammation in adipose tissue remain largely unknown. Methods: Sixty apolipoprotein E (ApoE^-/-) mice were randomly divided into chow and diabetes groups. Diabetes was induced by a high-fat and high-sugar diet combined with low-dose streptozotocin. Then we transferred a recombinant adenovirus carrying the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene into epididymal white adipose tissue (EWAT) of ApoE^-/- mice. After transfection, all mice were euthanized to evaluate the effects of PTPN2 on T cells polarization and atherosclerosis. Results: PTPN2 was downregulated in EWAT of diabetic ApoE^-/- mice. PTPN2 overexpression in EWAT reversed the high Th1/Treg and Th17/Treg ratios in EWAT of diabetic mice. In addition, PTPN2 overexpression in EWAT could significantly reduce macrophages infiltration, the ratio of M1/M2 macrophages and the expression of pro-inflammatory cytokines in EWAT, improving insulin resistance. In aortic root lesions, the vulnerability index were significantly decreased by overexpression of PTPN2 in EWAT. Conclusion: These data suggested that PTPN2 overexpression in EWAT would inhibit systemic inflammation and increase the plaque stability via T cells polarization shift in diabetic mice.

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PTPN2 inhibits the proliferation of psoriatic keratinocytes by dephosphorylation of STAT3

Liu,

Zhang

et al. 2024

Cell Biochemistry & Function

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Psoriasis is a recurrent and protracted disease that severely impacts the patient's physical and mental health. Thus, there is an urgent need to explore its pathogenesis to identify therapeutic targets. The expression level of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) was analyzed by immunohistochemistry techniques in psoriatic tissues and imiquimod‐induced psoriatic mouse models. PTPN2 and signal transducer and activator of transcription 3 (STAT3) were overexpressed or silenced in human keratinocytes or an interleukin (IL)‐6‐induced psoriasis HaCaT cell model using overexpression plasmid transfection or small interfering RNA technology in vitro, and the effects of PTPN2 on STAT3, HaCaT cell function, and autophagy levels were investigated using reverse transcription‐quantitative polymerase chain reaction, Western blot, Cell Counting Kit 8, 5‐ethynyl‐20‐deoxyuridine, flow cytometry, and transmission electron microscopy. PTPN2 expression was found to be significantly downregulated in psoriatic tissues. Then, the in vitro antipsoriatic properties of PTPN2 were investigated in an IL‐6‐induced psoriasis‐like cell model, and the results demonstrated that inhibition of keratinocyte proliferation by PTPN2 may be associated with elevated STAT3 dephosphorylation and autophagy levels. These findings provide novel insights into the mechanisms of autophagy in psoriatic keratinocytes and may be essential for developing new therapeutic strategies to improve inflammatory homeostasis in psoriatic patients.

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Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development

Cited by 34 publications

References 51 publications

The role of T‐cell protein tyrosine phosphatase in epithelial carcinogenesis

The role of T‐cell protein tyrosine phosphatase in epithelial carcinogenesis

Overexpression of PTPN2 in Visceral Adipose Tissue Ameliorated Atherosclerosis via T Cells Polarization Shift in Diabetic Apoe-/- Mice

PTPN2 inhibits the proliferation of psoriatic keratinocytes by dephosphorylation of STAT3

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