The Experts below are selected from a list of 176352 Experts worldwide ranked by ideXlab platform
Yoshiyuki Minegishi - One of the best experts on this subject based on the ideXlab platform.
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Hyperimmunoglobulin E syndrome and Tyrosine Kinase 2 deficiency.
Current opinion in allergy and clinical immunology, 2007Co-Authors: Yoshiyuki Minegishi, Hajime KarasuyamaAbstract:PURPOSE OF REVIEW The purpose of the review is to provide recent insight into the pathogenesis and pathophysiology of hyperimmunoglobulin E syndrome. RECENT FINDINGS We recently identified a homozygous four base-pair deletion in the coding region of the Tyrosine Kinase 2 gene in a hyperimmunoglobulin E syndrome patient who exhibited susceptibility to intracellular bacteria. SUMMARY Hyperimmunoglobulin E syndrome is a primary immunodeficiency characterized by recurrent staphylococcal skin abscesses and pneumonia, and elevated serum immunoglobulin E. This syndrome is subdivided into types 1 and 2. Type 1 displays abnormalities in multiple systems, including the skeletal/dental and immune systems, whereas type 2 abnormalities are confined to the immune system. We recently identified a homozygous mutation in the Tyrosine Kinase 2 gene in a type 2 patient. Analyses of cytokine responses in the patient's cells revealed that the Tyrosine Kinase 2 deficiency had resulted in severe impairment of the signal transduction for multiple cytokines, including interleukin-6, -10, -12 and -23, and interferon-alpha/beta. The cytokine signals were successfully restored by transducing the intact Tyrosine Kinase 2 gene. Thus, Tyrosine Kinase 2 plays obligatory roles in human immunity. Based on this finding, we propose that hyperimmunoglobulin E syndrome is a primary immunodeficiency caused by genetic alterations leading to the defect in multiple cytokine signals.
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Human Tyrosine Kinase 2 Deficiency Reveals Its Requisite Roles in Multiple Cytokine Signals Involved in Innate and Acquired Immunity
Immunity, 2006Co-Authors: Yoshiyuki Minegishi, Masako Saito, Tomohiro Morio, Ken Watanabe, Kazunaga Agematsu, Shigeru Tsuchiya, Hidetoshi Takada, Toshiro Hara, Nobuaki Kawamura, Tadashi ArigaAbstract:Tyrosine Kinase 2 (Tyk2) is a nonreceptor Tyrosine Kinase that belongs to the Janus Kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.
Yohei Mizuta - One of the best experts on this subject based on the ideXlab platform.
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Strong evidence of a combination polymorphism of the Tyrosine Kinase 2 gene and the signal transducer and activator of transcription 3 gene as a DNA-based biomarker for susceptibility to Crohn's disease in the Japanese population.
Journal of clinical immunology, 2009Co-Authors: Kayoko Sato, Mizuho Shiota, Sayaka Fukuda, Eiko Iwamoto, Haruhisa Machida, Tatsuo Inamine, Shinji Kondo, Katsunori Yanagihara, Hajime Isomoto, Yohei MizutaAbstract:Objective An association between susceptibility to inflammatory bowel disease (IBD) and polymorphisms of both the Tyrosine Kinase 2 gene (TYK2) and the signal transducer and activator of transcription 3 gene (STAT3) was examined in a Japanese population in order to identify the genetic determinants of IBD.
Hajime Karasuyama - One of the best experts on this subject based on the ideXlab platform.
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Hyperimmunoglobulin E syndrome and Tyrosine Kinase 2 deficiency.
Current opinion in allergy and clinical immunology, 2007Co-Authors: Yoshiyuki Minegishi, Hajime KarasuyamaAbstract:PURPOSE OF REVIEW The purpose of the review is to provide recent insight into the pathogenesis and pathophysiology of hyperimmunoglobulin E syndrome. RECENT FINDINGS We recently identified a homozygous four base-pair deletion in the coding region of the Tyrosine Kinase 2 gene in a hyperimmunoglobulin E syndrome patient who exhibited susceptibility to intracellular bacteria. SUMMARY Hyperimmunoglobulin E syndrome is a primary immunodeficiency characterized by recurrent staphylococcal skin abscesses and pneumonia, and elevated serum immunoglobulin E. This syndrome is subdivided into types 1 and 2. Type 1 displays abnormalities in multiple systems, including the skeletal/dental and immune systems, whereas type 2 abnormalities are confined to the immune system. We recently identified a homozygous mutation in the Tyrosine Kinase 2 gene in a type 2 patient. Analyses of cytokine responses in the patient's cells revealed that the Tyrosine Kinase 2 deficiency had resulted in severe impairment of the signal transduction for multiple cytokines, including interleukin-6, -10, -12 and -23, and interferon-alpha/beta. The cytokine signals were successfully restored by transducing the intact Tyrosine Kinase 2 gene. Thus, Tyrosine Kinase 2 plays obligatory roles in human immunity. Based on this finding, we propose that hyperimmunoglobulin E syndrome is a primary immunodeficiency caused by genetic alterations leading to the defect in multiple cytokine signals.
Wen Cheng Xiong - One of the best experts on this subject based on the ideXlab platform.
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Regulation of the formation of osteoclastic actin rings by proline-rich Tyrosine Kinase 2 interacting with gelsolin
The Journal of cell biology, 2003Co-Authors: Qiang Wang, Yi Xie, Xu Feng, Lin Mei, Jay M. Mcdonald, Wen Cheng XiongAbstract:Osteoclast activation is important for bone remodeling and is altered in multiple bone disorders. This process requires cell adhesion and extensive actin cytoskeletal reorganization. Proline-rich Tyrosine Kinase 2 (PYK2), a major cell adhesion–activated Tyrosine Kinase in osteoclasts, plays an important role in regulating this event. The mechanisms by which PYK2 regulates actin cytoskeletal organization and osteoclastic activation remain largely unknown. In this paper, we provide evidence that PYK2 directly interacts with gelsolin, an actin binding, severing, and capping protein essential for osteoclastic actin cytoskeletal organization. The interaction is mediated via the focal adhesion–targeting domain of PYK2 and an LD motif in gelsolin's COOH terminus. PYK2 phosphorylates gelsolin at Tyrosine residues and regulates gelsolin bioactivity, including decreasing gelsolin binding to actin monomer and increasing gelsolin binding to phosphatidylinositol lipids. In addition, PYK2 increases actin polymerization at the fibroblastic cell periphery. Finally, PYK2 interacts with gelsolin in osteoclasts, where PYK2 activation is required for the formation of actin rings. Together, our results suggest that PYK2 is a regulator of gelsolin, revealing a novel PYK2–gelsolin pathway in regulating actin cytoskeletal organization in multiple cells, including osteoclasts.
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Regulation of CDC42 GTPase by proline-rich Tyrosine Kinase 2 interacting with PSGAP, a novel pleckstrin homology and Src homology 3 domain containing rhoGAP protein
The Journal of cell biology, 2001Co-Authors: Xiu Rong Ren, Lin Mei, Yang Z. Huang, Wen Cheng XiongAbstract:Proline-rich Tyrosine Kinase 2 (PYK2), a Tyrosine Kinase structurally related to focal adhesion Kinase (FAK), is implicated in regulating cytoskeletal organization. However, mechanisms by which PYK2 participates in and regulates cytoskeletal organization remain largely unknown. Here we report identification of PSGAP, a novel protein that interacts with PYK2 and FAK and contains multiple domains including a pleckstrin homology domain, a rhoGTPase-activating protein domain, and a Src homology 3 domain. PYK2 interacts with PSGAP Src homology 3 domain via the carboxyl-terminal proline-rich sequence. PSGAP is able to increase GTPase activity of CDC42 and RhoA in vitro and in vivo. Remarkably, PYK2, but not FAK, can activate CDC42 via inhibition of PSGAP-mediated GTP hydrolysis of CDC42. Moreover, PSGAP is localized at cell periphery in fibroblasts in a pleckstrin homology domain–dependent manner. Over expression of PSGAP in fibroblasts results in reorganization of cytoskeletal structures and changes of cellular morphology, which requires rhoGTPase-activating activity. Taken together, our results suggest that PSGAP is a signaling protein essential for PYK2 regulation of cytoskeletal organization via Rho family GTPases.
Manfred Gemeiner - One of the best experts on this subject based on the ideXlab platform.
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A comparative proteome analysis links Tyrosine Kinase 2 (Tyk2) to the regulation of cellular glucose and lipid metabolism in response to poly(I:C).
Journal of proteomics, 2011Co-Authors: Tom Grunert, Nicole R. Leitner, Marta Radwan, Ingrid Miller, Martina Marchetti-deschmann, Thomas Kolbe, Claus Vogl, Barbara Wallner, Dagmar Kratky, Manfred GemeinerAbstract:Tyrosine Kinase 2 (Tyk2) is an integral part of the Janus Kinase-signal transducer and activator of transcription (JAK-STAT) pathway which relays intracellular signals of various cytokines. Tyk2 crucially contributes to host defense mechanisms against microbial pathogens and to tumor surveillance but also facilitates immune pathologies. Here we investigated the impact of Tyk2 on the macrophage proteome using the synthetic double-stranded RNA analog polyinosinic acid-polycytidylic acid (poly(I:C)) as a mimicry of viral infections. By means of 2D-DIGE in connection with PMF obtained by MALDI-MS and sequence tag determination by MS/MS we unambiguously identified eighteen protein spots corresponding to sixteen distinct proteins that are regulated by poly(I:C) and differentially expressed between wildtype (WT) and Tyk2-deficient macrophages. The majority of these proteins are functionally assigned to cellular immune responses and to metabolism. We show for selected metabolic enzymes, i.e. triosephosphate isomerase (TIM), ATP-citrate synthase (ACLY) and long-chain-fatty-acid-CoA ligase 4 (ACSL4), that Tyk2 affects protein expression transcriptionally and post-transcriptionally. We furthermore confirm the involvement of Tyk2 in the regulation of lipid and carbohydrate metabolism at the level of metabolites. Taken together, our results provide new evidence for important functions of Tyk2 at the molecular interface between innate immunity and cellular metabolism.
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The impact of Tyrosine Kinase 2 (Tyk2) on the proteome of murine macrophages and their response to lipopolysaccharide (LPS).
Proteomics, 2008Co-Authors: Marta Radwan, Tom Grunert, Ingrid Miller, Martina Marchetti-deschmann, Günter Allmaier, Thomas Kolbe, Claus Vogl, Niaobh O'donoghue, Michael J. Dunn, Manfred GemeinerAbstract:Tyrosine Kinase 2 (Tyk2) belongs to the Janus Kinase (Jak) family and is involved in signalling via a number of cytokines. Tyk2-deficient mice are highly resistant to lipopolysaccharide (LPS)-induced endotoxin shock. Macrophages are key players in the pathogenesis of endotoxin shock and, accordingly, defects in the LPS responses of Tyk2−/− macrophages have been reported. In the present study, the molecular role of Tyk2 is investigated in more detail using a proteomics approach. 2-D DIGE was applied to compare protein patterns from wild-type and Tyk2−/− macrophages and revealed significant differences in protein expression patterns between the genotypes before and after LPS treatment. Twenty-one proteins deriving from 25 differentially expressed spots were identified by MALDI/ESI MS. Among them, we show for N-myc interactor that its mRNA transcription/stability is positively influenced by Tyk2. In contrast, LPS-induced expression of plasminogen activator 2 protein but not mRNA is strongly enhanced in the absence of Tyk2. Our data furthermore suggest an influence of Tyk2 on the subcellular distribution of elongation factor 2 and on LPS-mediated changes in the peroxiredoxin 1 spot pattern. Thus, our results imply regulatory roles of Tyk2 at multiple levels and establish novel connections between Tyk2 and several cellular proteins.
