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Article ; Online: ACE2 in chronic disease and COVID-19: gene regulation and post-translational modification.

Wang, Chia-Wen / Chuang, Huai-Chia / Tan, Tse-Hua

2023 Volume 30, Issue 1, Page(s) 71

Abstract: Angiotensin-converting enzyme 2 (ACE2), a counter regulator of the renin-angiotensin system, provides protection against several chronic diseases. Besides chronic diseases, ACE2 is the host receptor for SARS-CoV or SARS-CoV-2 virus, mediating the first ... ...

Abstract	Angiotensin-converting enzyme 2 (ACE2), a counter regulator of the renin-angiotensin system, provides protection against several chronic diseases. Besides chronic diseases, ACE2 is the host receptor for SARS-CoV or SARS-CoV-2 virus, mediating the first step of virus infection. ACE2 levels are regulated by transcriptional, post-transcriptional, and post-translational regulation or modification. ACE2 transcription is enhanced by transcription factors including Ikaros, HNFs, GATA6, STAT3 or SIRT1, whereas ACE2 transcription is reduced by the transcription factor Brg1-FoxM1 complex or ERRα. ACE2 levels are also regulated by histone modification or miRNA-induced destabilization. The protein kinase AMPK, CK1α, or MAP4K3 phosphorylates ACE2 protein and induces ACE2 protein levels by decreasing its ubiquitination. The ubiquitination of ACE2 is induced by the E3 ubiquitin ligase MDM2 or UBR4 and decreased by the deubiquitinase UCHL1 or USP50. ACE2 protein levels are also increased by the E3 ligase PIAS4-mediated SUMOylation or the methyltransferase PRMT5-mediated ACE2 methylation, whereas ACE2 protein levels are decreased by AP2-mediated lysosomal degradation. ACE2 is downregulated in several human chronic diseases like diabetes, hypertension, or lung injury. In contrast, SARS-CoV-2 upregulates ACE2 levels, enhancing host cell susceptibility to virus infection. Moreover, soluble ACE2 protein and exosomal ACE2 protein facilitate SARS-CoV-2 infection into host cells. In this review, we summarize the gene regulation and post-translational modification of ACE2 in chronic disease and COVID-19. Understanding the regulation and modification of ACE2 may help to develop prevention or treatment strategies for ACE2-mediated diseases.
MeSH term(s)	Humans ; Angiotensin-Converting Enzyme 2/genetics ; Chronic Disease ; COVID-19/genetics ; Protein Processing, Post-Translational ; Protein Serine-Threonine Kinases ; Protein-Arginine N-Methyltransferases ; SARS-CoV-2
Chemical Substances	Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; MAP4K3 protein, human (EC 2.7.11.1) ; PRMT5 protein, human (EC 2.1.1.319) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Protein-Arginine N-Methyltransferases (EC 2.1.1.319) ; ACE2 protein, human (EC 3.4.17.23)
Language	English
Publishing date	2023-08-22
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1193378-1
ISSN	1423-0127 ; 1021-7770
ISSN (online)	1423-0127
ISSN	1021-7770
DOI	10.1186/s12929-023-00965-9
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Article ; Online: The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling.

Shih, Ying-Chun / Chen, Hsueh-Fen / Wu, Chia-Ying / Ciou, Yi-Ru / Wang, Chia-Wen / Chuang, Huai-Chia / Tan, Tse-Hua

Nature communications

2024 Volume 15, Issue 1, Page(s) 532

Abstract: DUSP22 is a dual-specificity phosphatase that inhibits T cell activation by inactivating the kinase Lck. Here we show that the E3 ubiquitin ligase UBR2 is a positive upstream regulator of Lck during T-cell activation. DUSP22 dephosphorylates UBR2 at ... ...

Abstract	DUSP22 is a dual-specificity phosphatase that inhibits T cell activation by inactivating the kinase Lck. Here we show that the E3 ubiquitin ligase UBR2 is a positive upstream regulator of Lck during T-cell activation. DUSP22 dephosphorylates UBR2 at specific Serine residues, leading to ubiquitin-mediated UBR2 degradation. UBR2 is also modified by the SCF E3 ubiquitin ligase complex via Lys48-linked ubiquitination at multiple Lysine residues. Single-cell RNA sequencing analysis and UBR2 loss of function experiments showed that UBR2 is a positive regulator of proinflammatory cytokine expression. Mechanistically, UBR2 induces Lys63-linked ubiquitination of Lck at Lys99 and Lys276 residues, followed by Lck Tyr394 phosphorylation and activation as part of TCR signalling. Inflammatory phenotypes induced by TCR-triggered Lck activation or knocking out DUSP22, are attenuated by genomic deletion of UBR2. UBR2-Lck interaction and Lck Lys63-linked ubiquitination are induced in the peripheral blood T cells of human SLE patients, which demonstrate the relevance of the UBR2-mediated regulation of inflammation to human pathology. In summary, we show here an important regulatory mechanism of T cell activation, which finetunes the balance between T cell response and aggravated inflammation.
MeSH term(s)	Humans ; Ubiquitination ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Phosphorylation ; Dual-Specificity Phosphatases/genetics ; Dual-Specificity Phosphatases/metabolism ; Inflammation/genetics ; Receptors, Antigen, T-Cell/metabolism ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism ; Mitogen-Activated Protein Kinase Phosphatases/genetics ; Mitogen-Activated Protein Kinase Phosphatases/metabolism
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Dual-Specificity Phosphatases (EC 3.1.3.48) ; Receptors, Antigen, T-Cell ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (EC 2.7.10.2) ; DUSP22 protein, human (EC 3.1.3.48) ; Mitogen-Activated Protein Kinase Phosphatases (EC 3.1.3.16) ; UBR2 protein, human (EC 2.3.2.27)
Language	English
Publishing date	2024-01-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-44843-w
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Article ; Online: UHRF1P contributes to IL-17A-mediated systemic lupus erythematosus via UHRF1-MAP4K3 axis.

Chuang, Huai-Chia / Lan, Kuei-Yuan / Hsu, Pu-Ming / Chen, Ming-Han / Chen, Yi-Ming / Yen, Jeng-Hsien / Liao, Ben-Yang / Tan, Tse-Hua

Journal of autoimmunity

2024 Volume 146, Page(s) 103221

Abstract: Inflammatory T cells contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Analysis of the T-cell transcriptomics data of two independent SLE patient cohorts by three machine learning models revealed the ... ...

Abstract	Inflammatory T cells contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Analysis of the T-cell transcriptomics data of two independent SLE patient cohorts by three machine learning models revealed the pseudogene UHRF1P as a novel SLE biomarker. The pseudogene-encoded UHRF1P protein was overexpressed in peripheral blood T cells of SLE patients. The UHRF1P protein lacks the amino-terminus of its parental UHRF1 protein, resulting in missing the proteasome-binding ubiquitin-like (Ubl) domain of UHRF1. T-cell-specific UHRF1P transgenic mice manifested the induction of IL-17A and autoimmune inflammation. Mechanistically, UHFR1P prevented UHRF1-induced Lys48-linked ubiquitination and degradation of MAP4K3 (GLK), which is a kinase known to induce IL-17A. Consistently, IL-17A induction and autoimmune phenotypes of UHRF1P transgenic mice were obliterated by MAP4K3 knockout. Collectively, UHRF1P overexpression in T cells inhibits the E3 ligase function of its parental UHRF1 and induces autoimmune diseases.
Language	English
Publishing date	2024-04-20
Publishing country	England
Document type	Journal Article
ZDB-ID	639452-8
ISSN	1095-9157 ; 0896-8411
ISSN (online)	1095-9157
ISSN	0896-8411
DOI	10.1016/j.jaut.2024.103221
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Article ; Online: Dual-specificity phosphatases 22-deficient T cells contribute to the pathogenesis of ankylosing spondylitis.

Chen, Ming-Han / Chuang, Huai-Chia / Yeh, Yi-Chen / Chou, Chung-Tei / Tan, Tse-Hua

BMC medicine

2023 Volume 21, Issue 1, Page(s) 46

Abstract: Background: Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study was to investigate the potential roles of ...

Abstract	Background: Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study was to investigate the potential roles of DUSPs in ankylosing spondylitis (AS). Methods: Sixty AS patients and 45 healthy controls were enrolled in this study. Associations of gene expression of 23 DUSPs in peripheral T cells with inflammatory cytokine gene expression and disease activity of AS were analyzed. Finally, we investigated whether the characteristics of AS are developed in DUSP-knockout mice. Results: The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in peripheral T cells were significantly higher in AS group than those of healthy controls (all p < 0.05), while DUSP22 (also named JKAP) mRNA levels were significantly lower in AS group than healthy controls (p < 0.001). The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in T cells were positively correlated with mRNA levels of tumor necrosis factor-α (TNF-α), whereas DUSP22 was inversely correlated (all p < 0.05). In addition, inverse correlations of DUSP22 gene expression in peripheral T cells with C-reactive protein, erythrocyte sedimentation rate, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were observed (all p < 0.05). More importantly, aged DUSP22 knockout mice spontaneously developed syndesmophyte formation, which was accompanied by an increase of TNF-α Conclusions: DUSP22 may play a crucial role in the pathogenesis and regulation of disease activity of AS.
MeSH term(s)	Animals ; Mice ; Dual-Specificity Phosphatases/genetics ; Dual-Specificity Phosphatases/metabolism ; Mice, Knockout ; RNA, Messenger ; Spondylitis, Ankylosing/genetics ; T-Lymphocytes ; Tumor Necrosis Factor-alpha
Chemical Substances	Dual-Specificity Phosphatases (EC 3.1.3.48) ; Dusp14 protein, mouse (EC 3.1.3.48) ; RNA, Messenger ; Tumor Necrosis Factor-alpha ; DUSP22 protein, human (EC 3.1.3.48) ; Dusp22 protein, mouse (EC 3.1.3.48)
Language	English
Publishing date	2023-02-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2131669-7
ISSN	1741-7015 ; 1741-7015
ISSN (online)	1741-7015
ISSN	1741-7015
DOI	10.1186/s12916-023-02745-6
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Article ; Online: MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus.

Chuang, Huai-Chia / Tan, Tse-Hua

Cells

2019 Volume 8, Issue 11

Abstract: T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), which is a severe autoimmune disease. In the past 60 years, only one new therapeutic agent with limited efficacy has been approved for SLE treatment; therefore, the ... ...

Abstract	T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), which is a severe autoimmune disease. In the past 60 years, only one new therapeutic agent with limited efficacy has been approved for SLE treatment; therefore, the development of early diagnostic biomarkers and therapeutic targets for SLE is desirable. Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) and dual-specificity phosphatases (DUSPs) are regulators of MAP kinases. Several MAP4Ks and DUSPs are involved in T-cell signaling and autoimmune responses. HPK1 (MAP4K1), DUSP22 (JKAP), and DUSP14 are negative regulators of T-cell activation. Consistently, HPK1 and DUSP22 are downregulated in the T cells of human SLE patients. In contrast, MAP4K3 (GLK) is a positive regulator of T-cell signaling and T-cell-mediated immune responses. MAP4K3 overexpression-induced RORγt-AhR complex specifically controls interleukin 17A (IL-17A) production in T cells, leading to autoimmune responses. Consistently, MAP4K3 and the RORγt-AhR complex are overexpressed in the T cells of human SLE patients, as are DUSP4 and DUSP23. In addition, DUSPs are also involved in either human autoimmune diseases (DUSP2, DUSP7, DUSP10, and DUSP12) or T-cell activation (DUSP1, DUSP5, and DUSP14). In this review, we summarize the MAP4Ks and DUSPs that are potential biomarkers and/or therapeutic targets for SLE.
MeSH term(s)	Animals ; Autoimmunity ; Biomarkers ; Disease Susceptibility ; Dual-Specificity Phosphatases/genetics ; Dual-Specificity Phosphatases/metabolism ; Gene Expression Regulation ; Humans ; Lupus Erythematosus, Systemic/diagnosis ; Lupus Erythematosus, Systemic/etiology ; Lupus Erythematosus, Systemic/metabolism ; Lupus Erythematosus, Systemic/therapy ; Lymphocyte Activation ; MAP Kinase Kinase Kinases/genetics ; MAP Kinase Kinase Kinases/metabolism ; Models, Biological ; Molecular Targeted Therapy ; Multigene Family ; Prognosis ; Signal Transduction ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
Chemical Substances	Biomarkers ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP3K21 protein, human (EC 2.7.11.25) ; Dual-Specificity Phosphatases (EC 3.1.3.48)
Language	English
Publishing date	2019-11-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells8111433
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Article ; Online: MAP4K3/GLK in autoimmune disease, cancer and aging.

Chuang, Huai-Chia / Tan, Tse-Hua

Journal of biomedical science

2019 Volume 26, Issue 1, Page(s) 82

Abstract: MAP4K3 (also named GLK) is a serine/threonine kinase, which belongs to the mammalian Ste20-like kinase family. At 22 years of age, GLK was initially cloned and identified as an upstream activator of the MAPK JNK under an environmental stress and ... ...

Abstract	MAP4K3 (also named GLK) is a serine/threonine kinase, which belongs to the mammalian Ste20-like kinase family. At 22 years of age, GLK was initially cloned and identified as an upstream activator of the MAPK JNK under an environmental stress and proinflammatory cytokines. The data derived from GLK-overexpressing or shRNA-knockdown cell lines suggest that GLK may be involved in cell proliferation through mTOR signaling. GLK phosphorylates the transcription factor TFEB and retains TFEB in the cytoplasm, leading to inhibition of cell autophagy. After generating and characterizing GLK-deficient mice, the important in vivo roles of GLK in T-cell activation were revealed. In T cells, GLK directly interacts with and activates PKCθ through phosphorylating PKCθ at Ser-538 residue, leading to activation of IKK/NF-κB. Thus, GLK-deficient mice display impaired T-cell-mediated immune responses and decreased inflammatory phenotypes in autoimmune disease models. Consistently, the percentage of GLK-overexpressing T cells is increased in the peripheral blood from autoimmune disease patients; the GLK-overexpressing T cell population is correlated with disease severity of patients. The pathogenic mechanism of autoimmune disease by GLK overexpression was unraveled by characterizing T-cell-specific GLK transgenic mice and using biochemical analyses. GLK overexpression selectively promotes IL-17A transcription by inducing the AhR-RORγt complex in T cells. In addition, GLK overexpression in cancer tissues is correlated with cancer recurrence of human lung cancer and liver cancer; the predictive power of GLK overexpression for cancer recurrence is higher than that of pathologic stage. GLK directly phosphorylates and activates IQGAP1, resulting in induction of Cdc42-mediated cell migration and cancer metastasis. Furthermore, treatment of GLK inhibitor reduces disease severity of mouse autoimmune disease models and decreases IL-17A production of human autoimmune T cells. Due to the inhibitory function of HPK1/MAP4K1 in T-cell activation and the promoting effects of GLK on tumorigenesis, HPK1 and GLK dual inhibitors could be useful therapeutic drugs for cancer immunotherapy. In addition, GLK deficiency results in extension of lifespan in Caenorhabditis elegans and mice. Taken together, targeting MAP4K3 (GLK) may be useful for treating/preventing autoimmune disease, cancer metastasis/recurrence, and aging.
MeSH term(s)	Aging/genetics ; Autoimmune Diseases/genetics ; Humans ; Neoplasms/genetics ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism
Chemical Substances	MAP4K3 protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2019-10-22
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1193378-1
ISSN	1423-0127 ; 1021-7770
ISSN (online)	1423-0127
ISSN	1021-7770
DOI	10.1186/s12929-019-0570-5
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Article ; Online: Dual-specificity phosphatases 22-deficient T cells contribute to the pathogenesis of ankylosing spondylitis

Ming-Han Chen / Huai-Chia Chuang / Yi-Chen Yeh / Chung-Tei Chou / Tse-Hua Tan

BMC Medicine, Vol 21, Iss 1, Pp 1-

2023 Volume 15

Abstract: Abstract Background Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study was to investigate the potential ... ...

Abstract	Abstract Background Dual-specificity phosphatases (DUSPs) can dephosphorylate both tyrosine and serine/threonine residues of their substrates and regulate T cell-mediated immunity and autoimmunity. The aim of this study was to investigate the potential roles of DUSPs in ankylosing spondylitis (AS). Methods Sixty AS patients and 45 healthy controls were enrolled in this study. Associations of gene expression of 23 DUSPs in peripheral T cells with inflammatory cytokine gene expression and disease activity of AS were analyzed. Finally, we investigated whether the characteristics of AS are developed in DUSP-knockout mice. Results The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in peripheral T cells were significantly higher in AS group than those of healthy controls (all p < 0.05), while DUSP22 (also named JKAP) mRNA levels were significantly lower in AS group than healthy controls (p < 0.001). The mRNA levels of DUSP4, DUSP5, DUSP6, DUSP7, and DUSP14 in T cells were positively correlated with mRNA levels of tumor necrosis factor-α (TNF-α), whereas DUSP22 was inversely correlated (all p < 0.05). In addition, inverse correlations of DUSP22 gene expression in peripheral T cells with C-reactive protein, erythrocyte sedimentation rate, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were observed (all p < 0.05). More importantly, aged DUSP22 knockout mice spontaneously developed syndesmophyte formation, which was accompanied by an increase of TNF-α+, interleukin-17A+, and interferon-γ+ CD3+ T cells. Conclusions DUSP22 may play a crucial role in the pathogenesis and regulation of disease activity of AS.
Keywords	DUSP22 ; Ankylosing spondylitis ; Tumor necrosis factor-α ; Interferon-γ ; Interleukin-17A ; Medicine ; R
Subject code	610
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: DUSP6 Deficiency Attenuates Neurodegeneration after Global Cerebral Ischemia.

Weng, Yi-Chinn / Huang, Yu-Ting / Chiang, I-Chen / Chuang, Huai-Chia / Lee, Tsong-Hai / Tan, Tse-Hua / Chou, Wen-Hai

International journal of molecular sciences

2023 Volume 24, Issue 9

Abstract: Transient global cerebral ischemia (tGCI) resulting from cardiac arrest causes selective neurodegeneration in hippocampal CA1 neurons. Although the effect is clear, the underlying mechanisms directing this process remain unclear. Previous studies have ... ...

Abstract	Transient global cerebral ischemia (tGCI) resulting from cardiac arrest causes selective neurodegeneration in hippocampal CA1 neurons. Although the effect is clear, the underlying mechanisms directing this process remain unclear. Previous studies have shown that phosphorylation of Erk1/2 promotes cell survival in response to tGCI. DUSP6 (also named MKP3) serves as a cytosolic phosphatase that dephosphorylates Erk1/2, but the role of DUSP6 in tGCI has not been characterized. We found that DUSP6 was specifically induced in the cytoplasm of hippocampal CA1 neurons 4 to 24 h after tGCI. DUSP6-deficient mice showed normal spatial memory acquisition and retention in the Barnes maze. Impairment of spatial memory acquisition and retention after tGCI was attenuated in DUSP6-deficient mice. Neurodegeneration after tGCI, revealed by Fluoro-Jade C and H&E staining, was reduced in the hippocampus of DUSP6-deficient mice and DUSP6 deficiency enhanced the phosphorylation and nuclear translocation of Erk1/2 in the hippocampal CA1 region. These data support the role of DUSP6 as a negative regulator of Erk1/2 signaling and indicate the potential of DUSP6 inhibition as a novel therapeutic strategy to treat neurodegeneration after tGCI.
MeSH term(s)	Animals ; Mice ; Brain Ischemia/genetics ; CA1 Region, Hippocampal ; Cerebral Infarction ; Hippocampus ; Ischemic Attack, Transient ; Neurons
Chemical Substances	Dusp6 protein, mouse (EC 3.1.3.48)
Language	English
Publishing date	2023-04-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24097690
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Article ; Online: MAP4K3/GLK in autoimmune disease, cancer and aging

Huai-Chia Chuang / Tse-Hua Tan

Journal of Biomedical Science, Vol 26, Iss 1, Pp 1-

2019 Volume 8

Abstract: Abstract MAP4K3 (also named GLK) is a serine/threonine kinase, which belongs to the mammalian Ste20-like kinase family. At 22 years of age, GLK was initially cloned and identified as an upstream activator of the MAPK JNK under an environmental stress and ...

Abstract	Abstract MAP4K3 (also named GLK) is a serine/threonine kinase, which belongs to the mammalian Ste20-like kinase family. At 22 years of age, GLK was initially cloned and identified as an upstream activator of the MAPK JNK under an environmental stress and proinflammatory cytokines. The data derived from GLK-overexpressing or shRNA-knockdown cell lines suggest that GLK may be involved in cell proliferation through mTOR signaling. GLK phosphorylates the transcription factor TFEB and retains TFEB in the cytoplasm, leading to inhibition of cell autophagy. After generating and characterizing GLK-deficient mice, the important in vivo roles of GLK in T-cell activation were revealed. In T cells, GLK directly interacts with and activates PKCθ through phosphorylating PKCθ at Ser-538 residue, leading to activation of IKK/NF-κB. Thus, GLK-deficient mice display impaired T-cell-mediated immune responses and decreased inflammatory phenotypes in autoimmune disease models. Consistently, the percentage of GLK-overexpressing T cells is increased in the peripheral blood from autoimmune disease patients; the GLK-overexpressing T cell population is correlated with disease severity of patients. The pathogenic mechanism of autoimmune disease by GLK overexpression was unraveled by characterizing T-cell-specific GLK transgenic mice and using biochemical analyses. GLK overexpression selectively promotes IL-17A transcription by inducing the AhR-RORγt complex in T cells. In addition, GLK overexpression in cancer tissues is correlated with cancer recurrence of human lung cancer and liver cancer; the predictive power of GLK overexpression for cancer recurrence is higher than that of pathologic stage. GLK directly phosphorylates and activates IQGAP1, resulting in induction of Cdc42-mediated cell migration and cancer metastasis. Furthermore, treatment of GLK inhibitor reduces disease severity of mouse autoimmune disease models and decreases IL-17A production of human autoimmune T cells. Due to the inhibitory function of HPK1/MAP4K1 in T-cell ...
Keywords	MAP4K3 (GLK) ; HPK1 ; Autoimmune disease ; Cancer metastasis ; Aging ; IL-17A ; Medicine ; R
Subject code	610
Language	English
Publishing date	2019-10-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Association of TRAIL receptor with phosphatase SHP-1 enables repressing T cell receptor signaling and T cell activation through inactivating Lck.

Chyuan, I-Tsu / Liao, Hsiu-Jung / Tan, Tse-Hua / Chuang, Huai-Chia / Chu, Yu-Chuan / Pan, Meng-Hsun / Wu, Chien-Sheng / Chu, Ching-Liang / Sheu, Bor-Ching / Hsu, Ping-Ning

Journal of biomedical science

2024 Volume 31, Issue 1, Page(s) 33

Abstract: Background: T cell receptor (TCR) signaling and T cell activation are tightly regulated by gatekeepers to maintain immune tolerance and avoid autoimmunity. The TRAIL receptor (TRAIL-R) is a TNF-family death receptor that transduces apoptotic signals to ... ...

Abstract	Background: T cell receptor (TCR) signaling and T cell activation are tightly regulated by gatekeepers to maintain immune tolerance and avoid autoimmunity. The TRAIL receptor (TRAIL-R) is a TNF-family death receptor that transduces apoptotic signals to induce cell death. Recent studies have indicated that TRAIL-R regulates T cell-mediated immune responses by directly inhibiting T cell activation without inducing apoptosis; however, the distinct signaling pathway that regulates T cell activation remains unclear. In this study, we screened for intracellular TRAIL-R-binding proteins within T cells to explore the novel signaling pathway transduced by TRAIL-R that directly inhibits T cell activation. Methods: Whole-transcriptome RNA sequencing was used to identify gene expression signatures associated with TRAIL-R signaling during T cell activation. High-throughput screening with mass spectrometry was used to identify the novel TRAIL-R binding proteins within T cells. Co-immunoprecipitation, lipid raft isolation, and confocal microscopic analyses were conducted to verify the association between TRAIL-R and the identified binding proteins within T cells. Results: TRAIL engagement downregulated gene signatures in TCR signaling pathways and profoundly suppressed phosphorylation of TCR proximal tyrosine kinases without inducing cell death. The tyrosine phosphatase SHP-1 was identified as the major TRAIL-R binding protein within T cells, using high throughput mass spectrometry-based proteomics analysis. Furthermore, Lck was co-immunoprecipitated with the TRAIL-R/SHP-1 complex in the activated T cells. TRAIL engagement profoundly inhibited phosphorylation of Lck (Y394) and suppressed the recruitment of Lck into lipid rafts in the activated T cells, leading to the interruption of proximal TCR signaling and subsequent T cell activation. Conclusions: TRAIL-R associates with phosphatase SHP-1 and transduces a unique and distinct immune gatekeeper signal to repress TCR signaling and T cell activation via inactivating Lck. Thus, our results define TRAIL-R as a new class of immune checkpoint receptors for restraining T cell activation, and TRAIL-R/SHP-1 axis can serve as a potential therapeutic target for immune-mediated diseases.
MeSH term(s)	Humans ; Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Jurkat Cells ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism ; Signal Transduction ; Protein Tyrosine Phosphatases/genetics ; Protein Tyrosine Phosphatases/metabolism ; Phosphorylation ; Lymphocyte Activation ; Tyrosine/metabolism
Chemical Substances	Receptors, TNF-Related Apoptosis-Inducing Ligand ; Receptors, Antigen, T-Cell ; Protein Tyrosine Phosphatase, Non-Receptor Type 6 (EC 3.1.3.48) ; Protein Tyrosine Phosphatases (EC 3.1.3.48) ; Tyrosine (42HK56048U)
Language	English
Publishing date	2024-03-27
Publishing country	England
Document type	Journal Article
ZDB-ID	1193378-1
ISSN	1423-0127 ; 1021-7770
ISSN (online)	1423-0127
ISSN	1021-7770
DOI	10.1186/s12929-024-01023-8
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