Kenji Oritani

Osaka City University, Ōsaka, Ōsaka, Japan

Are you Kenji Oritani?

Claim your profile

Publications (108)591.4 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that regulates immune and inflammatory responses through interactions with a variety of signaling and transcriptional molecules. In the current study, we clarified the physiological role of STAP-2 in mast cell function, a key mediator of IgE-associated allergic responses. STAP-2 is constitutively expressed in mast cells. STAP-2 deficiency in mast cells greatly enhances FcεRI-mediated signals, resulting in the increased tyrosine phosphorylation of the phospholipase C-γ isoform, calcium mobilization, and degranulation. Of importance, STAP-2-deficient mice challenged with DNP-BSA after passive sensitization with anti-DNP IgE show more severe rectal temperature decrease than do wild-type mice. STAP-2-deficient mice also show increased vascular permeability and more severe cutaneous anaphylaxis after DNP-BSA injection. These regulatory functions performed by STAP-2 indicate that there is an interaction between STAP-2 and FcεRI. In addition, our previous data indicate that STAP-2 binds to the phospholipase C-γ isoform and IκB kinase-β. Therefore, our data described in this article strongly suggest that manipulation of STAP-2 expression in mast cells may control the pathogenesis of allergic diseases and have the potential for treating patients with allergy.
    The Journal of Immunology 03/2014; · 5.52 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Signal-transducing adaptor protein-2 (STAP-2) was cloned as a c-fms/M-CSF receptor-interacting protein. STAP-2 is an adaptor protein carrying pleckstrin homology- and Src homology 2-like domains, as well as a YXXQ motif. STAP-2 has been indicated to have an ability to bind and modulate a variety of signaling and transcriptional molecules. Especially, our previous in vitro studies showed that STAP-2 is crucial for immune and/or inflammatory responses.Here, we have investigated the role of STAP-2 in intestinal inflammation in vivo. The disruption of STAP-2 attenuates dextran sodium sulfate-induced colitis via inhibition of macrophage recruitment. To study whether hematopoietic or epithelial cell-derived STAP-2 is required to this phenomenon, we generated BM chimeric mice. STAP-2 deficient macrophages impair the ability of CXCL12-induced migration. Intriguingly, STAP-2 also regulates production of proinflammatory chemokines and cytokines such as CXCL1 and TNF-α from intestinal epithelial cells. Therefore, STAP-2 has a potential to regulate plural molecular events during pathological inflammatory responses. Furthermore, our findings not only indicate that STAP-2 is important in regulating intestinal inflammation, but also provide new insights toward the development of novel therapeutic approaches.This article is protected by copyright. All rights reserved
    European Journal of Immunology 03/2014; · 4.97 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Anamorsin (AM), an anti-apoptotic molecule, confers factor-independent survival on hematopoietic cells. AM-deficient (AM(-/-)) mice are embryonic lethal due to a defect in definitive hematopoiesis. However, the significance of AM in embryonic hematopoiesis remains unknown. This study characterized the hematopoietic defects in AM(-/-) fetal livers. The AM(-/-) fetal liver displayed significantly reduced numbers of c-Kit(+) Sca-1(+) Lin(-) (KSL) cells. An in vitro colony-forming unit assay showed that fetal liver cells isolated from AM(-/-) embryos gave rise to fewer colonies in all cell types. Primary and secondary transplantations with AM(-/-)cells were markedly inefficient in the reconstitution of all lineages. Furthermore, the limiting dilution assay revealed that fetal liver hematopoietic stem cell function was impaired due to AM deficiency. The reconstitution activity in AM(-/-) hematopoietic stem cells (HSCs) was markedly reduced in all lineages. Furthermore the limiting dilution assay revealed that the number of fetal liver HSCs was reduced due to AM deficiency. Retrovirus-mediated AM expression rescued the defective hematopoietic colony-forming activities of AM(-/-) KSL cells. We also investigated the effects of AM deficiency on fetal liver stromal cells, which support hematopoiesis. Interestingly, primary stromal cell cultures from wild-type fetal liver supported the growth of AM(-/-) KSL cells, but stromal cultures from AM(-/-) fetal liver provided little support of wild-type KSL cell growth. These results demonstrated that AM was essential for both autonomous and extrinsic regulation of fetal liver hematopoiesis. This study provided new insight into the molecular regulation of hematopoiesis.
    Experimental hematology 01/2014; · 3.11 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Tyrosine kinase 2 (Tyk2), a member of the Jak kinase family, mediates signals triggered by various cytokines, which are related to the pathogenesis of psoriasis. In this study, we investigated the role of Tyk2 in IL-23-induced psoriasis-like skin inflammation. Tyk2(-/-) mice when injected with IL-23 showed significantly reduced ear skin swelling with epidermal hyperplasia and inflammatory cell infiltration compared with wild-type mice. In addition, Tyk2 deficiency reduced production of pro-inflammatory cytokines and psoriasis-relevant anti-microbial peptides. More noteworthy is that Tyk2 directly regulated IL-22-dependent inflammation and epidermal hyperplasia. Taken together with the inhibition of IL-23-induced inflammation by treatment with neutralizing antibodies against IL-17 or IL-22, Tyk2 participates in both IL-23 and IL-22 signal transduction to mediate psoriasis-like skin inflammation. On the basis of these findings, we demonstrated for the first time that a small-molecule Tyk2 inhibitor significantly inhibited IL-23-induced inflammation and cytokine production in the skin. These observations demonstrate the important role of Tyk2 in experimental skin inflammation and indicate the therapeutic potential of Tyk2 inhibition in human psoriasis.
    International Immunology 12/2013; · 3.14 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Degradation of IFNR protein is one of the mechanisms to limit the extent of cellular responses to interferons. Tyrosine kinase 2 (TYK2), a JAK family kinase, has been reported to bind to and stabilize IFNR, indicating that TYK2 is a fundamental component of IFN receptor complex. Herein, we identified Jun activation domain-binding protein 1 (JAB1) as a new TYK2 binding partner and investigated its role in the regulation of IFN responses. siRNA knockdown of JAB1 resulted in suppression of IFN-induced phosphorylation of STAT proteins and their transcriptional activation. Importantly, JAB1 knockdown induced the activation of SCF ubiquitin ligase complex containing Cullin 1 (CUL1), as judged by the enhancement of covalent modification of CUL1 with the ubiquitin-like protein NEDD8, and markedly reduced the basal protein level of IFNR. In contrast, NEDD8 knockdown or inhibition of NEDD8-modification by NEDD8-activating enzyme (NAE) inhibitor resulted in increased IFNR protein concomitantly with reduction of NEDD8-modified CUL1. Furthermore, NAE inhibitor treatment enhanced the susceptibility to IFN-α in HeLa cells. These data suggest that the NEDD8 modification pathway is involved in the proteolysis of IFNAR1 and that JAB1 acts as a positive regulator of IFN responses by stabilizing IFNR through antagonizing the NEDD8 pathway.
    Journal of Biological Chemistry 09/2013; · 4.65 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Although Y14 is known to be a component of the exon junction complex, we previously reported that Y14 regulates IL-6-induced STAT3 activation. In this study, we showed that endogenous Y14 positively regulated TNF-α-induced IL-6 expression in HeLa cells. Small interfering RNA-mediated Y14-knockdown reduced TNF-α-induced and NF-κB-mediated transcriptional activity, phosphorylation/degradation of IκBα, and nuclear localization of NF-κB/p65. As in the case of IL-6 stimuli, Y14 enhanced TNF-α-induced STAT3 phosphorylation, which is important for its nuclear retention. However, our manipulation of Y14 expression indicated that it is involved in TNF-α-induced IL-6 expression via both STAT3-dependent and -independent mechanisms. We screened signaling molecules in the TNF-α-NF-κB pathway and found that Y14 endogenously associated with receptor-interacting protein 1 (RIP1) and TNFR-associated death domain (TRADD). Overexpression of RIP1, but not TRADD, restored TNF-α-induced NF-κB activation in Y14-knockdown cells, and Y14 overexpression restored TNF-α-induced NF-κB activation in TRADD-knockdown cells, but not in RIP1-knockdown cells, indicating that Y14 lies downstream of TRADD and upstream of RIP1. Of importance, Y14 significantly enhanced the binding between RIP1 and TRADD, and this is a possible new mechanism for Y14-mediated modification of TNF-α signals. Although Y14 associates with MAGOH in the exon junction complex, Y14's actions in the TNF-α-NF-κB pathway are unlikely to require MAGOH. Therefore, Y14 positively regulates signals for TNF-α-induced IL-6 production at multiple steps beyond an exon junction complex protein.
    The Journal of Immunology 07/2013; · 5.52 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: How hematopoietic stem cells (HSCs) produce particular lineages is insufficiently understood. We searched for key factors that direct HSC to lymphopoiesis. Comparing gene expression profiles for HSCs and early lymphoid progenitors revealed that Satb1, a global chromatin regulator, was markedly induced with lymphoid lineage specification. HSCs from Satb1-deficient mice were defective in lymphopoietic activity in culture and failed to reconstitute T lymphopoiesis in wild-type recipients. Furthermore, Satb1 transduction of HSCs and embryonic stem cells robustly promoted their differentiation toward lymphocytes. Whereas genes that encode Ikaros, E2A, and Notch1 were unaffected, many genes involved in lineage decisions were regulated by Satb1. Satb1 expression was reduced in aged HSCs with compromised lymphopoietic potential, but forced Satb1 expression partly restored that potential. Thus, Satb1 governs the initiating process central to the replenishing of lymphoid lineages. Such activity in lymphoid cell generation may be of clinical importance and useful to overcome immunosenescence.
    Immunity 06/2013; · 19.80 Impact Factor
  • Source
    01/2013; , ISBN: 978-953-51-1107-8
  • [show abstract] [hide abstract]
    ABSTRACT: Whereas most hematopoietic stem cells (HSC) are quiescent in homeostasis, they actively proliferate in response to bone marrow (BM) injury. Signals from the BM microenvironment are thought to promote entry of HSC into the cell cycle. However, it has been cumbersome to assess cycle status of viable HSC and thus explore unique features associated with division. In this study, we show that expression of endothelial cell-selective adhesion molecule (ESAM) can be a powerful indicator of HSC activation. ESAM levels clearly mirrored the shift of HSC between quiescence and activation, and it was prominent in comparison with other HSC-related Ags. ESAM(hi) HSC were actively dividing, but had surprisingly high long-term reconstituting capacity. Immunohistochemical analyses showed that most ESAM(hi) HSC were located near vascular endothelium in the BM after 5-fluorouracil treatment. To determine the importance of ESAM in the process of BM recovery, ESAM knockout mice were treated with 5-fluorouracil and their hematopoietic reconstruction was examined. The ESAM deficiency caused severe and prolonged BM suppression, suggesting that ESAM is functionally indispensable for HSC to re-establish homeostatic hematopoiesis. With respect to intracellular regulators, NF-κB and topoisomerase II levels correlated with the ESAM upregulation. Thus, our data demonstrate that the intensity of ESAM expression is useful to trace activated HSC and to understand molecular events involved in stem cell states.
    The Journal of Immunology 05/2012; 189(1):200-10. · 5.52 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: We found that an adaptor protein, signal-transducing adaptor protein (STAP)-2, is a new member of the Fas-death-inducing signaling complex and participates in activation-induced cell death in T cells. STAP-2 enhanced Fas-mediated apoptosis and caspase-8 aggregation and activation in Jurkat T cells. Importantly, STAP-2 directly interacted with caspase-8 and Fas, resulting in enhanced interactions between caspase-8 and FADD in the Fas-death-inducing signaling complex. Moreover, STAP-2 protein has a consensus caspase-8 cleavage sequence, VEAD, in its C-terminal domain, and processing of STAP-2 by caspase-8 was crucial for Fas-induced apoptosis. Physiologic roles of STAP-2 were confirmed by observations that STAP-2-deficient mice displayed impaired activation-induced cell death and superantigen-induced T cell depletion. Therefore, STAP-2 is a novel participant in the regulation of T cell apoptosis after stimulation.
    The Journal of Immunology 05/2012; 188(12):6194-204. · 5.52 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Sir2 has been shown to be essential for transcriptional silencing and longevity provided by calorie restriction in Saccharomyces cerevisiae and Caenorhabditis elegans. In this study, we investigated the role for its mammalian homologue, SIRT1, in hematopoietic cells. SIRT1 inhibitor, nicotinamide (NA), promoted and its activator, resveratrol, inhibited the differentiation of murine bone marrow c-Kit(high)Sca-1(+)Lineage(-) (KSL) cells during the culture system ex vivo. To further clarify the roles of SIRT1 in hematopoietic cells, we isolated KSL cells from fetal liver of SIRT1 knockout (KO) mice and cultured them for 5days, because SIRT1 KO mice die shortly after the delivery. In agreement with the results from the experiments using NA and resveratrol, KSL cells isolated from SIRT1 KO mice more apparently differentiated and lost the KSL phenotype than those from wild-type (WT) mice. Furthermore, in each of colony assay, replating assay, or serial transplantation assay, SIRT1 KO KSL cells lost earlier the characteristics of stem cells than WT KSL cells. In addition, we found that SIRT1 maintains prematurity of hematopoietic cells through ROS elimination, FOXO activation, and p53 inhibition. These results suggest that SIRT1 suppresses differentiation of hematopoietic stem/progenitor cells and contributes to the maintenance of stem cell pool.
    Biochemical and Biophysical Research Communications 02/2012; 418(4):811-7. · 2.41 Impact Factor
  • Source
    01/2012; , ISBN: 978-953-307-930-1
  • [show abstract] [hide abstract]
    ABSTRACT: In chronic myeloid leukemia (CML), the BCR-ABL fusion oncoprotein activates multiple pathways involved in cell survival, growth promotion and disease progression. In this report, we show that the signal-transducing adaptor protein-2 (STAP-2) is involved in BCR-ABL activity. We demonstrate that STAP-2 bound to BCR-ABL, and BCR and ABL proteins, depending on the STAP-2 Src homology 2-like domain. BCR-ABL phosphorylates STAP-2 Tyr250 and the phosphorylated STAP-2 in turn upregulated BCR-ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK (extracellular-signal-regulated kinase), STAT5 (signal transducer and activator of transcription 5), BCL-xL (B-cell lymphoma-extra large) and BCL-2(B-cell lymphoma 2). In addition, STAP-2 interacts with BCR-ABL to alter chemokine receptor expression leading to downregulation of CXCR4 and upregulation of CCR7. The interaction between STAP-2 and BCR-ABL plays a crucial role in conferring a growth advantage and resistance to imatinib, a BCR-ABL inhibitor, as well as tumor progression. Notably, mice injected with BCR-ABL/STAP-2-expressing Ba/F3 cells developed lymph node enlargement and hepatosplenomegaly. Moreover, suppression of STAP-2 in K562 CML cells resulted in no tumor formation in mice. Our results demonstrate a critical contribution of STAP-2 in BCR-ABL activity, and suggest that STAP-2 might be an important candidate for drug development for patients with CML. Furthermore, the expression of STAP-2 provides useful information for estimating the characteristics of individual CML clones.
    Oncogene 01/2012; 31(40):4384-96. · 7.36 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Tyrosine kinase-2 (Tyk2) participates in the signaling pathways of multiple cytokines in innate and acquired immunity. In the present study, we investigated the in vivo involvement of Tyk2 in anti-type II collagen antibody-induced arthritis (CAIA) using Tyk2-deficient mice. Hind paws of wild-type mice showed massive swelling and erythema by arthritogenic antibody injection, whereas Tyk2-deficient mice did not show any signs of arthritis. Indeed, neither the infiltration of inflammatory cells nor the fibrillation of articular cartilages was observed in Tyk2-deficient mice. Tyk2 deficiency also reduced the production of T(h)1/T(h)17-related cytokines, the other proinflammatory cytokines and matrix metalloproteases, which are induced in the CAIA paw. Our results demonstrate a critical contribution of Tyk2 in the development of arthritis, and we propose that Tyk2 might be an important candidate for drug development.
    International Immunology 09/2011; 23(9):575-82. · 3.14 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Krüppel-associated box-associated protein 1 (KAP1) is thought to act mainly as a scaffold for protein complexes, which together silence transcription by triggering the formation of heterochromatin. Using small interfering RNA-mediated KAP1 knockdown, we found that endogenous KAP1 negatively regulated TNF-α-induced IL-6 production in HeLa cells. KAP1 is likely to modulate the binding of NF-κB to the IL-6 promoter because KAP1 knockdown enhanced TNF-α-induced NF-κB-luciferase activity, but not IκBα degradation. Of importance, we found negative regulatory effects of KAP1 on the serine phosphorylation of STAT3, the acetylation of NF-κB/p65 by p300, and the nuclear localization of NF-κB/p65. In addition, KAP1 associated with NF-κB/p65 and inhibited the binding between NF-κB/p65 and p300. Thus, KAP1 is likely to negatively control the acetylation of NF-κB/p65, which is critical for its nuclear retention. Taken together, KAP1 modulated the acetylation of NF-κB/p65 by interfering with the interactions among STAT3, p300, and NF-κB/p65, resulting in reduced IL-6 production after TNF-α stimulation. Our findings that KAP1 directly interacts with transcriptional factors are new, and will inform further research to elucidate KAP1 function.
    The Journal of Immunology 09/2011; 187(5):2476-83. · 5.52 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Tyrosine kinase-2 (Tyk2), a member of the Jak family of kinases, mediates the signals triggered by various cytokines, including type I IFNs, IL-12, and IL-23. In the current study, we investigated the in vivo involvement of Tyk2 in several IL-12/Th1- and IL-23/Th17-mediated models of experimental diseases, including methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis. In these disease models, Tyk2 deficiency influenced the phenotypes in immunity and/or inflammation. Our findings demonstrate a somewhat broader contribution of Tyk2 to immune systems than previously expected and suggest that Tyk2 may represent an important candidate for drug development by targeting both the IL-12/Th1 and IL-23/Th17 axes.
    The Journal of Immunology 07/2011; 187(1):181-9. · 5.52 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Zipper-interacting protein kinase (ZIPK) is a widely expressed serine/threonine kinase that has been implicated in apoptosis and transcriptional regulation. Here, we identified Nemo-like kinase (NLK) as a novel ZIPK-binding partner, and found that ZIPK regulates NLK-mediated repression of canonical Wnt/beta-catenin signaling. Indeed, siRNA-mediated reduction of endogenous ZIPK expression reduced Wnt/beta-catenin signaling. Furthermore, ZIPK affected complex formation of NLK-T-cell factor (TCF) 4. Importantly, ZIPK siRNA treatment in human colon carcinoma cells resulted in a reduction of beta-catenin/TCF-mediated gene expression and cell growth. These results indicate that ZIPK may serve as a transcriptional regulator of canonical Wnt/beta-catenin signaling through interaction with NLK/TCF4.
    Journal of Biological Chemistry 03/2011; · 4.65 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: It would be of great value to predict the efficacy of tyrosine kinase inhibitors (TKIs) in the treatment of individual CML patients. We propose an immunoblot system for detecting the phosphorylation of Crkl, a major target of Bcr-Abl, in blood samples after in vitro incubation with TKIs. When the remaining phosphorylated Crkl after treatment with imatinib was evaluated as the "residual index (RI)", high values were found in accordance with imatinib resistance. Moreover, RI reflected the outcome of imatinib- as well as second generation TKIs with a high sensitivity and specificity. Therefore, this system should be useful in the selection of TKIs.
    Leukemia research 03/2011; 35(9):1205-11. · 2.36 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Zipper-interacting protein kinase (ZIPK) is a widely expressed serine/threonine kinase that has been implicated in apoptosis and transcriptional regulation. Here, we identified Nemo-like kinase (NLK) as a novel ZIPK-binding partner and found that ZIPK regulates NLK-mediated repression of canonical Wnt/β-catenin signaling. Indeed, siRNA-mediated reduction of endogenous ZIPK expression reduced Wnt/β-catenin signaling. Furthermore, ZIPK affected the formation of NLK-T-cell factor 4 (TCF4) complex. Importantly, ZIPK siRNA treatment in human colon carcinoma cells resulted in a reduction of β-catenin/TCF-mediated gene expression and cell growth. These results indicate that ZIPK may serve as a transcriptional regulator of canonical Wnt/β-catenin signaling through interaction with NLK/TCF4.
    Journal of Biological Chemistry 03/2011; 286(21):19170-7. · 4.65 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: STAP-2 (signal transducing adaptor protein-2) is a recently identified adaptor protein that contains pleckstrin homology (PH) and Src homology 2-like domains, as well as a STAT3-binding motif in its C-terminal region. STAP-2 is also a substrate of breast tumor kinase (Brk). In breast cancers, Brk expression is deregulated and promotes STAT3-dependent cell proliferation. In the present study, manipulated STAP-2 expression demonstrated essential roles of STAP-2 in Brk-mediated STAT3 activation. STAP-2 interacts with both Brk and STAT3. In addition, small interfering RNA-mediated reduction of endogenous STAP-2 expression strongly decreased Brk-mediated STAT3 activation in T47D breast cancer cells. The PH domain of STAP-2 is involved in multiple steps: the binding between Brk and STAP-2, the activation and tyrosine phosphorylation of STAT3, and the activation of Brk. Notably, a STAP-2 PH-Brk fusion protein exhibited robust kinase activity and increased activation and tyrosine phosphorylation of STAT3. Finally, STAP-2 knockdown in T47D cells induced a significant decrease of proliferation, as strong as that of Brk or STAT3 knockdown. Taken together, our findings are likely to inform the development of a novel therapeutic strategy, as well as the determination of novel prognostic values, in breast carcinomas.
    Journal of Biological Chemistry 12/2010; 285(49):38093-38103. · 4.65 Impact Factor

Publication Stats

3k Citations
591.40 Total Impact Points

Institutions

  • 2005–2014
    • Osaka City University
      • Graduate School of Medicine
      Ōsaka, Ōsaka, Japan
  • 2003–2013
    • Hokkaido University
      • • Graduate School of Pharmaceutical Sciences
      • • Department of Immunobiology
      Sapporo-shi, Hokkaido, Japan
  • 2000–2012
    • Osaka University
      • • Division of Hematology and Oncology
      • • Department of Integrated Medicine
      • • Division of Environmental and Molecular Medicine
      Suika, Ōsaka, Japan
  • 2011
    • Miyazaki University
      • Department of Internal Medicine 3
      Миядзаки, Miyazaki, Japan
  • 1995–2010
    • Oklahoma Medical Research Foundation
      • Immunobiology and Cancer Program
      Oklahoma City, OK, United States