研究者詳細 - 吉村　昭彦

論文 - 吉村　昭彦

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Loss of mammalian Sprouty2 leads to enteric neuronal hyperplasia and esophageal achalasia

Taketomi Takaharu, Yoshiga Daigo, Taniguchi Koji, Kobayashi Takashi, Nonami Atsushi, Kato Reiko, Sasaki Mika, Sasaki Atsuo, Ishibashi Hitoshi, Moriyama Maiko, Nakamura Kei Ichiro, Nishimura Junji, Yoshimura Akihiko

Nature Neuroscience 8 （ 7 ） 855 - 857 2005年07月

ISSN 1097-6256

We report here that loss of the Sprouty2 gene (also known as Spry2) in mice resulted in enteric nerve hyperplasia, which led to esophageal achalasia and intestinal pseudo-obstruction. Glial cell line-derived neurotrophic factor (GDNF) induced hyperactivation of ERK and Akt in enteric nerve cells. Anti-GDNF antibody administration corrected nerve hyperplasia in Sprouty2-deficient mice. We show Sprouty2 to be a negative regulator of GDNF for the neonatal development or survival of enteric nerve cells. © 2005 Nature Publishing Group.

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The neuropeptide neuromedin U promotes inflammation by direct activation of mast cells

Moriyama Maiko, Sato Takahiro, Inoue Hiromasa, Fukuyama Satoru, Teranishi Hitoshi, Kangawa Kenji, Kano Tatsuhiko, Yoshimura Akihiko, Kojima Masayasu

Journal of Experimental Medicine 202 （ 2 ） 217 - 224 2005年07月

ISSN 0022-1007

Neuromedin U (NMU) is a neuropeptide that is expressed in the gastrointestinal tract and central nervous system. NMU interacts with two G protein-coupled receptors, NMU-R1 and NMU-R2. Whereas NMU-R2 localizes predominantly to nerve cells, NMU-R1 is expressed in peripheral tissues including lymphocytes and monocytes, suggesting a role of NMU in immunoregulation. However, the functions of NMU in peripheral tissues have not been clarified. In this study, using NMU-deficient mice, we first demonstrated that NMU plays an important role in mast cell-mediated inflammation. Complete Freund's adjuvant-induced mast cell degranulation as well as edema and neutrophil infiltration, which occurred weakly in mast cell-deficient WBB6F ₁ - W/W^v mice, did not occur in NMU-deficient mice. Moreover, intraplantar injection of NMU into paws induced early inflammatory responses such as mast cell degranulation, vasodilation, and plasma extravasation in WT mice but not in WBB6F₁ - W/W^v mice. NMU-R1 was highly expressed in primary mast cells, and NMU induced Ca ²⁺ mobilization and degranulation in peritoneal mast cells. These data indicate that NMU promotes mast cell-mediated inflammation; therefore, NMU receptor antagonists could be a novel target for pharmacological inhibition of mast cell-mediated inflammatory diseases. © The Rockefeller University Press.

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WSX-1 over-expression in CD4⁺ T cells leads to hyperproliferation and cytokine hyperproduction in response to TCR stimulation

Takeda Atsunobu, Hamano Shinjiro, Shiraishi Hiroshi, Yoshimura Takeru, Ogata Hisanobu, Ishii Kazunari, Ishibashi Tatsuro, Yoshimura Akihiko, Yoshida Hiroki

International Immunology 17 （ 7 ） 889 - 897 2005年07月

ISSN 0953-8178

WSX-1 is a component of the IL-27R. Analyses of WSX-1 knockout (WSX-1^-/-) mice have shown that IL-27/WSX-1 signaling is essential for the proper development of T_h1 responses and that WSX-1 can suppress cellular activation and pro-inflammatory cytokine production. We have generated transgenic mouse lines over-expressing the WSX-1 gene under the control of the T cell-specific CD2 promoter (WSX-1 Tg mice). Unexpectedly, like activated CD4⁺ T cells from WSX-1^-/- mice, activated CD4⁺ T cells from WSX-1 Tg mice showed increased proliferation, augmented IL-2 production and up-regulated surface expression of activation markers. IL-27-mediated tyrosine phosphorylation of STAT1 was also enhanced in WSX-1 Tg CD4⁺ T cells, but STAT3 activation was normal. Exogenous IL-27 supported the proliferation of wild-type CD4⁺ T cells but suppressed that of WSX-1 Tg cells. WSX-1 over-expression increased IFN-γ production in T_h1-polarized CD4⁺ T cells, but also promoted T_h2 cytokine production under T_h 1-polarizing conditions. Importantly, WSX-1 over-expression failed to suppress T_h2 cytokine production under T_h 2-polarizing conditions. Cytokine hyperproduction was also observed in vivo in WSX-1 Tg mice injected with Con A. Our data suggest that WSX-1 plays a pivotal role in regulating T cell responsiveness to TCR stimulation and that the correct balance of STAT1/STAT3 activation downstream of IL-27R engagement is crucial for the physiological function of IL-27. © The Japanese Society for Immunology 2005. All rights reserved.

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Negative regulation of cytokine signaling and immune responses by SOCS proteins

Yoshimura Akihiko, Nishinakamura Hitomi, Matsumura Yumiko, Hanada Toshikatsu

Arthritis Research and Therapy 7 （ 3 ） 100 - 110 2005年06月

ISSN 1478-6354

Immune and inflammatory systems are controlled by multiple cytokines, including interleukins and interferons. Many of these cytokines exert their biological functions through JAKs (Janus tyrosine kinases) and STAT (signal transduction and activators of transcription) transcription factors. CIS (cytokine-inducible SH2 (Src homology 2) protein) and SOCS (suppressor of cytokine signaling) are a family of intracellular proteins, several of which have emerged as key physiological regulators of cytokine-mediated homeostasis, including innate and adaptive immunity. In this review we focus on the molecular mechanism of the action of CIS/SOCS family proteins and their roles in immune regulation and inflammatory diseases including rheumatoid arthritis. © 2005 BioMed Central Ltd.

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Negative regulation of cytokine signaling

Yoshimura Akihiko

Clinical Reviews in Allergy and Immunology 28 （ 3 ） 205 - 220 2005年06月

ISSN 1080-0549

Immune and inflammatory systems are controlled by multiple cytokines, including interleukins and interferons. Many of these cytokines exert their biological functions through Janus kinases and signal transducers and activators of transcription factors. The cytokine-inducible SH2 protein (CIS) and suppressors of cytokine signaling (SOCS) are members of a family of intracellular proteins, several of which have emerged as key physiological regulators of cytokine-mediated homeostasis, including innate and adaptive immunity. This article focuses on the molecular mechanism of the action of CIS/SOCS family proteins and their roles in immune regulation and inflammatory diseases. © Copyright 2005 by Humana Press Inc.

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Induction of hyper Th1 cell-type immune responses by dendritic cells lacking the suppressor of cytokine signaling-1 gene

Hanada Toshikatsu, Tanaka Kentaro, Matsumura Yumiko, Yamauchi Moriyasu, Nishinakamura Hitomi, Aburatani Hiroyuki, Mashima Ryuichi, Kubo Masato, Kobayashi Takashi, Yoshimura Akihiko

Journal of Immunology 174 （ 7 ） 4325 - 4332 2005年04月

ISSN 0022-1767

Suppressor of cytokine signaling (SOCS1/JAB) has been shown to play an important role in regulating dendritic cell (DC) function and suppressing inlammatory diseases and systemic autoimmunity. However, role of SOCS1 in DCs for the initiation of Th cell response has not been clarified. Here we demonstrate that SOCS1-deficient DCs induce stronger Th1-type responses both in vitro and in vivo. SOCS1-deficient DCs induced higher IFN-γ production from naive T cells than wild-type (WT) DCs in vitro. Lymph node T cells also produced a higher amount of IFN-γ when SOCS1-deficient bone marrow-derived DCs (BMDCs) were transferred in vivo. Moreover, SOCS1^-/- BMDCs raised more effective anti-tumor immunity than WT BMDCs. Microarray analysis revealed that IFN-inducible genes were highly expressed in SOCS1-deficient DCs without IFN stimulation, suggesting hyper STAT1 activation in SOCS1 ^-/- DCs. These phenotypes of SOCS1-deicient DCs were similar to those of CD8α⁺ DCs, and in the WT spleen, SOCS1 is expressed at higher levels in the Th2-inducing CD4⁺ DC subset, relative to the Th1-inducing CD8α⁺ DC subset. We propose that reduction of the SOCS1 gene expression in DCs leads to CD8α⁺ DC-like phenotype which promotes Th1-type hyperresponses. Copyright © 2005 by The American Association of Immunologists, Inc.

Stat5a inhibits IL-12-induced Th1 cell differentiation through the induction of suppressor of cytokine signaling expression

Takatori Hiroaki, Nakajima Hiroshi, Kagami Shin Ichiro, Hirose Koichi, Suto Akira, Suzuki Kotaro, Kubo Masato, Yoshimura Akihiko, Saito Yasushi, Iwamoto Itsuo

Journal of Immunology 174 （ 7 ） 4105 - 4112 2005年04月

ISSN 0022-1767

In previous studies, we have shown that Th2 cell differentiation is diminished but Th1 cell differentiation is increased in Stat5a-deficient (Stat5a^-/-) CD4⁺ T cells. In the present study, we clarified the molecular mechanisms of Stat5a-mediated Th cell differentiation. We found that enhanced Th1 cell differentiation and the resultant IFN-γ production played a dominant inhibitory role in the down-regulation of IL-4-induced Th2 cell differentiation of Stat5a^-/- CD4⁺ T cells. We also found that IL-12-induced Stat4 phosphorylation and Th1 cell differentiation were augmented in Stat5a^-/- CB4⁺ T cells. Importantly, the expression of suppressor of cytokine signaling (SOCS)3, a potent inhibitor of IL-12-induced Stat4 activation, was decreased in Stat5a ^-/- CD4⁺ T cells. Moreover, a reporter assay showed that a constitutively active form of Stat5a but not Stat6 activated the SOCS3 promoter. Furthermore, chromatin immunoprecipitation assays revealed that Stat5a binds to the SOCS3 promoter in CD4⁺ T cells. Finally, the retrovirus-mediated expression of SOCS3 restored the impaired Th cell differentiation of Stat5a^-/- CD4⁺ T cells. These results suggest that Stat5a forces the Th1/Th2 balance toward a Th2-type by preventing IL-12-induced Th1 cell differentiation through the induction of SOCS3. Copyright © 2005 by The American Association of Immunologists, Inc.

Modulation of TLR signalling by the C-terminal Src kinase (Csk) in macrophages

Aki Daisuke, Mashima Ryuichi, Saeki Kazuko, Minoda Yasumasa, Yamauchi Moriyasu, Yoshimura Akihiko

Genes to Cells 10 （ 4 ） 357 - 368 2005年04月

ISSN 1356-9597

In macrophages and monocytes, lipopolysaccharide (LPS) triggers the production of pro-inflammatory cytokine through Toll-like receptor (TLR) 4. Although major TLR signalling pathways are mediated by serine or threonine kinases including IKK, TAK1, p38 and JNKs, a number of reports suggested that tyrosine phosphorylation of intracellular proteins is involved in LPS signalling. Here, we identified several tyrosine-phosphorylated proteins using mass spectrometric analysis in response to LPS stimulation. Among these proteins, we characterized C-terminal Src kinase (Csk), which negatively regulates Src-like kinases in RAW 264.7 cells using RNAi knockdown technology. Unexpectedly, LPS-induced CD40 activation and the secretion of pro-inflammatory cytokine such as IL-6 and TNF-α, was down-regulated in Csk knockdown cells. Furthermore, overall cellular tyrosine phosphorylation and TLR4-mediated activation of IκB-α, Erk and p38 but not of JNK, were also down-regulated in Csk knockdown cells. The protein expression levels of a tyrosine kinase, Fgr, were reduced in Csk knockdown cells, suggesting that Csk is a critical regulator of TLR4-mediated signalling by modifying the levels of Src-like kinases. © Blackwell Publishing Limited.

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Regulation of dendritic cell activation and autoimmunity by SOCS1

Hanada Toshikatsu, Yoshimura Akihiko

Nishinihon Journal of Urology 67 （ 4 ） 168 - 175 2005年04月

ISSN 0029-0726

The suppressor of cytokine signaling-1 (SOCS1/JAB) negatively regulates not only the cytokine-signaling pathway, but also lipopolysaccharide (LPS)-induced macrophage activation. We found that SOCS1-deficient dendritic cells (DCs) were also hyperresponsive to interferon-γ (IFNγ) and interleukin-4 (IL-4). To define the role of SOCS1-deficient DCs in vivo, we generated mice in which the SOCS1 expression was restored in T and B cells under a SOCS1 ^-/- background. In these mice, DCs were accumulated in the thymus and spleen and produced high levels of BAFF/BLyS, resulting in the aberrant expansion of B cells and autoreactive antibody production. SOCS1-deficient DCs efficiently stimulated B cell proliferation in vitro and auto-antibody production in vivo. These results indicate that SOCS1 plays an essential role in the normal DC functions and in the suppression of systemic autoimmunity.

Keeping DCs awake by putting SOCS1 to sleep

Kobayashi Takashi, Yoshimura Akihiko

Trends in Immunology 26 （ 4 ） 177 - 179 2005年04月

ISSN 1471-4906

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Physical and functional interactions between STAP-2/BKS and STAT5

Sekine Yuichi, Yamamoto Tetsuya, Yumioka Taro, Sugiyama Kenji, Tsuji Satoshi, Oritani Kenji, Shimoda Kazuya, Minoguchi Mayu, Yoshimura Akihiko, Matsuda Tadashi

Journal of Biological Chemistry 280 （ 9 ） 8188 - 8196 2005年03月

ISSN 0021-9258

Signal-transducing adaptor protein family of proteins (STAPs), which currently contains two members, are proposed to be adaptor molecules because of their pleckstrin homology (PH) and Src-homology 2 (SH2)-like domains. STAP-1 has been shown to interact with STAT5 and the tyrosine kinase Tec. With regard to STAP-2/BKS functions, immunoprecipitation experiments and intracellular stainings revealed STAP-2/BKS binds STAT5 in several types of cells. Mutational studies revealed that the PH- and SH2-like domains of STAP-2/BKS interacted with the C-terminal region of STAT5. STAP-2/BKS and STAT5 were found to constitutively co-localize in the cytoplasm of resting cells, but STAP-2/BKS was found to dissociate upon STAT5 phosphorylation, suggesting a role in regulating signaling of STAT5. The physiological role of these interactions is not fully understood, but in studies of overexpression of STAP-2/BKS, cytokine-induced tyrosine phosphorylation and transcriptional activation of STAT5 was diminished. In addition, thymocytes from STAP-2/BKS-deficient mice showed the enhanced interleukin-2-dependent cell growth. Taken together, STAP-2/BKS is an additional modulator of STAT5-mediated signaling. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

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Suppressors of cytokine signaling-1 and -3 regulate osteoclastogenesis in the presence of inflammatory cytokines

Ohishi Masanobu, Matsumura Yumiko, Aki Daisuke, Mashima Ryuichi, Taniguchi Koji, Kobayashi Takashi, Kukita Toshio, Iwamoto Yukihide, Yoshimura Akihiko

Journal of Immunology 174 （ 5 ） 3024 - 3031 2005年03月

ISSN 0022-1767

Bone metabolism and the immune system have a correlative relationship, and both are controlled by various common cytokines, such as IFNs and ILs, produced in the bone microenvironments. The suppressor of cytokine signaling-1 (SOCS1) and SOCS3 are negative regulators of such cytokines. Although SOCSs are shown to be induced during osteoclast differentiation, their physiological roles in osteoclast differentiation and function have not been clarified. Thus, we examined the roles of SOCS1 and SOCS3 in Osteoclastogenesis using SOCS1- and SOCS3-deficient mice. IFN-γ-mediated inhibition of osteoclast differentiation from bone marrow-derived monocytes (BMMs) was strongly enhanced in SOCS1-deflcient BMMs, but was diminished in SOCS1-overexpressing BMMs. Moreover, LPS-induced Osteoclastogenesis and bone destruction in vivo were suppressed in SOCS1^+/- mice compared with those in wild-type mice, suggesting that SOCS1 antagonizes the inhibitory effect of IFN-γ on Osteoclastogenesis. SOCS3 did not alter the inhibitory effect of IFNs in Osteoclastogenesis in both gain and loss of functional assays; however, the suppressive effect of IL-6 on osteoclast differentiation was greater in SOCS3-deficient BMMs than in wild-type BMMs in vitro. In addition, IL-6 significantly prevented LPS-induced bone destruction in SOCS3-deficient mice, although it failed in wild-type mice in vivo. In SOCS3-deficient BMMs, expression levels of TNF-receptor-associated factor-6 and IκB were drastically reduced and receptor activator of the NF-κB ligand-induced IκB phospliorylation was severely impaired in the presence of IL-6. These data suggest that both SOCS1 and SOCS3 regulate osteoclastogenesis by blocking the inhibitory effect of inflammatory cytokines on receptor activator of the NF-κB ligand-mediated osteoclast differentiation signals. Selective suppression of SOCS1 and SOCS3 in osteoclast precursors may be a possible therapeutic strategy for inflammatory bone destruction.

SOCS3/CIS3 negative regulation of STAT3 in HGF-induced keratinocyte migration

Tokumaru Sho, Sayama Koji, Yamasaki Kenshi, Shirakata Yuji, Hanakawa Yasushi, Yahata Yoko, Dai Xiuju, Tohyama Mikiko, Yang Lujun, Yoshimura Akihiko, Hashimoto Koji

Biochemical and Biophysical Research Communications 327 （ 1 ） 100 - 105 2005年02月

ISSN 0006-291X

Hepatocyte growth factor (HGF) is a potent mitogen for mature hepatocytes. Because HGF has strong effects on the motility of keratinocytes and is produced by fibroblasts, HGF is thought to regulate keratinocyte migration during wound healing. However, the intracellular signaling mechanism of HGF-induced keratinocyte migration is poorly understood. In this report, we clarify the roles of STAT3 and SOCS/CIS family in HGF-induced keratinocyte migration. HGF activated STAT3 and strongly induced keratinocyte migration. Transfection with the dominant-negative mutant of STAT3 almost completely abolished HGF-induced keratinocyte migration and STAT3 phosphorylation. Next, we studied the mechanisms that regulate STAT3 phosphorylation. HGF enhanced the expression of SOCS3/CIS3 by sixfold within 1 h, but had minimum effect on SOCS1/JAB expression. Transfection with SOCS3/CIS3 almost completely abolished HGF-induced STAT3 phosphorylation and keratinocyte migration, indicating that SOCS3/CIS3 acts as a negative regulator of HGF-induced keratinocyte migration. In conclusion, SOCS3/CIS3 regulates HGF-induced keratinocyte migration by inhibiting STAT3 phosphorylation. © 2004 Elsevier Inc. All rights reserved.

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Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness

Inoue Hiromasa, Kato Reiko, Fukuyama Satoru, Nonami Atsushi, Taniguchi Kouji, Matsumoto Koichiro, Nakano Takako, Tsuda Miyuki, Matsumura Mikiko, Kubo Masato, Ishikawa Fumihiko, Moon Byoung Gon, Takatsu Kiyoshi, Nakanishi Yoichi, Yoshimura Akihiko

Journal of Experimental Medicine 201 （ 1 ） 73 - 82 2005年01月

ISSN 0022-1007

T helper 2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, play a critical role in allergic asthma. These cytokines transmit signals through the Janus kinase/signal transducer and activator of transcription (STAT) and the Ras-extracellular signal-regulated kinase (ERK) signaling pathways. Although the suppressor of cytokine signaling (SOCS) family proteins have been shown to regulate the STAT pathway, the mechanism regulating the ERK pathway has not been clarified. The Sprouty-related Ena/VASP homology 1-domain-containing protein (Spred)-1 has recently been identified as a negative regulator of growth factor-mediated, Ras-dependent ERK activation. Here, using Spred-1 -deficient mice, we demonstrated that Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness, without affecting helper T cell differentiation. Biochemical assays indicate that Spred-1 suppresses IL-5-dependent cell proliferation and ERK activation. These data indicate that Spred-1 negatively controls eosinophil numbers and functions by modulating IL-5 signaling in allergic asthma.

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Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes

Takahashi Nobuki, Saito Yoshihiko, Kuwahara Koichiro, Harada Masaki, Tanimoto Keiji, Nakagawa Yasuaki, Kawakami Rika, Nakanishi Michio, Yasuno Shinji, Usami Satoru, Yoshimura Akihiko, Nakao Kazuwa

Journal of Molecular and Cellular Cardiology 38 （ 1 ） 185 - 192 2005年01月

ISSN 0022-2828

gp130-dependent signaling is known to play a critical role in the onset of heart failure. In that regard, cardiotrophin-1 (CT-1) activates several signaling pathways via gp130, and induces hypertrophy in neonatal rat cardiomyocytes. Among the mediators activated by CT-1, STAT3 is thought to be important for induction of cell hypertrophy, though its precise function in the CT-1 signaling pathway is not fully understood. In the present study, therefore, to better understand the significance of STAT3 activity in CT-1 signaling, we infected cultured cardiomyocytes with adenoviral vectors harboring a dominant-negative STAT3 mutant or one of two endogenous negative regulators of cytokine signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways [suppressor of cytokine signaling (SOCS) 1 and 3] and then examined their effects on three indexes of CT-1-induced cell hypertrophy: protein synthesis, secretion of brain natriuretic peptide and changes in cell surface area. In control cells, CT-1-induced both STAT3 phosphorylation and cell hypertrophy. Overexpression of dominant-negative STAT3 mutant suppressed CT-1-induced STAT3 phosphorylation, but did not affect cell hypertrophy. On the other hand overexpression of SOCS1 or SOCS3 inhibited both CT-1-induced STAT3 phosphorylation and cell hypertrophy. CT-1 also induced phosphorylations of ERK1/2 and ERK5 in cardiomyocytes, and those, too, were suppressed by overexpression of SOCSs. CT-1-induced cell hypertrophy was suppressed by overexpression of a dominant-negative MEK5 mutant, and not by overexpression of a dominant-negative MEK1 mutant. These findings indicate that the major pathway responsible for the hypertrophic responses to CT-1 is not JAK-STAT3 pathway nor MEK1-ERK1/2 pathway, but MEK5-ERK5 pathway. © 2004 Elsevier Ltd. All rights reserved.

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SOCS1/JAB likely mediates the protective effect of cardiotrophin-1 against lipopolysaccharide-induced left ventricular dysfunction in vivo

Tanimoto Keiji, Saito Yoshihiko, Hamanaka Ichiro, Kuwahara Koichiro, Harada Masaki, Takahashi Nobuki, Kawakami Rika, Nakagawa Yasuaki, Nakanishi Michio, Adachi Yuichiro, Shirakami Gotaro, Fukuda Kazuhiko, Yoshimura Akihiko, Nakao Kazuwa

Circulation Journal 69 （ 11 ） 1412 - 1417 2005年

ISSN 1346-9843

Background: Suppressor of cytokine signaling 1 (SOCS1) is a negative regulator of cytokine signaling whose expression is induced in the rat heart by cardiotrophin-1 (CT-1). Sepsis-induced myocardial depression results from the expression of inducible nitric oxide synthase (iNOS) evoked by inflammatory cytokines. Methods and Results: The effect of CT-1 on lipopolysaccharide (LPS)-induced cardiac dysfunction was examined in a rat model of sepsis. In the absence of CT-1, LPS (1 mg/kg ip) elicited a reduction of systolic function and dilation of the ventricular cavity within 3-6 h after administration. These physiological effects were accompanied by increased ventricular phosphorylation of signal transducers and activators of transcription (STAT) 1 and STAT3, activation of nuclear factor-^• B^• and expression of iNOS mRNA. Notably, administration of CT-1 (20^• g ^•/kg iv) immediately prior to LPS significantly inhibited all of these LPS-induced changes. To determine whether SOCS1 expression in cardiomyocytes is sufficient to inhibit LPS- and cytokine-induced expression of iNOS mRNA, the effects of forced expression of SOCS1 in cultured neonatal cardiomyocytes were investigated using an adenovirus-mediated transfection system. Forced expression of SOCS1 significantly inhibited iNOS transcription induced by LPS, tumor necrosis factor-^• ^•or interferon-^•.^• Conclusions: CT-1-mediated expression of SOCS1 in cardiomyocytes may be a useful target for preventing sepsis-induced myocardial depression.

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Receptor tyrosine kinases (c-kit, c-fmns, Flt-3, Tie2, etc.)

Yoshimura Akihiko, Sanada Masato, Mashima Ryuichi

Nippon rinsho. Japanese journal of clinical medicine 63 Suppl 4 207 - 214 2005年

ISSN 0047-1852

Negative regulation of cytokine and TLR signalings by SOCS and others

Naka Tetsuji, Fujimoto Minoru, Tsutsui Hiroko, Yoshimura Akihiko

Advances in Immunology 87 61 - 122 2005年

ISSN 0065-2776

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Activation and translocation of PKCδ is necessary for VEGF-induced ERK activation through KDR in HEK293T cells

Kuriyama Masamitsu, Taniguchi Taizo, Shirai Yasuhito, Sasaki Atsuo, Yoshimura Akihiko, Saito Naoaki

Biochemical and Biophysical Research Communications 325 （ 3 ） 843 - 851 2004年12月

ISSN 0006-291X

VEGF-KDR/Flk-1 signal utilizes the phospholipase C-γ-protein kinase C (PKC)-Raf-MEK-ERK pathway as the major signaling pathway to induce gene expression and cPLA2 phosphorylation. However, the spatio-temporal activation of a specific PKC isoform induced by VEGF-KDR signal has not been clarified. We used HEK293T (human embryonic kidney) cells expressing transiently KDR to examine the activation mechanism of PKC. PKC specific inhibitors and human PKCδ knock-down using siRNA method showed that PKCδ played an important role in VEGF-KDR-induced ERK activation. Myristoylated alanine-rich C-kinase substrate (MARCKS) translocates from the plasma membrane to the cytoplasm depending upon phosphorylation by PKC. Translocation of MARCKS-GFP induced by VEGF-KDR stimulus was blocked by rottlerin, a PKCδ specific inhibitor, or human PKCδ siRNA. VEGF-KDR stimulation did not induce ERK phosphorylation in human PKCδ-knockdown HEK293T cells, but co-expression of rat PKCδ-GFP recovered the ERK phosphorylation. Y311/332F mutant of rat PKCδ-GFP which cannot be activated by tyrosine-phosphorylation but activated by DAG recovered the ERK phosphorylation, while C1B-deletion mutant of rat PKCδ-GFP, which can be activated by tyrosine-phosphorylation but not by DAG, failed to recover the ERK phosphorylation in human PKCδ-knockdown HEK293T cell. These results indicate that PKCδ is involved in VEGF-KDR-induced ERK activation via C1B domain. © 2004 Published by Elsevier Inc.

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Erratum

Kamio Masaki, Yoshida Takafumi, Ogata Hisanobu, Douchi Tsutomu, Nagata Yukihiro, Inoue Makoto, Hasegawa Mamoru, Yonemitsu Yoshikazu, Yoshimura Akihiko

Oncogene 23 （ 58 ） 9449 2004年12月

ISSN 0950-9232

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論文 - 吉村　昭彦