| 1. |
Yada Y, Matsumoto M, Inoue T, Baba A, Higuchi R, Kawai C, Yanagisawa M, Kitamura D, Ohga S, Kurosaki T, Baba Y. , STIM-mediated calcium influx regulates maintenance and selection of germinal center B cells., J. Exp. Med., 2024.01. |
| 2. |
Ono C, Tanaka S, Myouzen K, Iwasaki T, Ueda M, Oda Y, Yamamoto K, Kochi Y, Baba Y., Upregulated Fcrl5 disrupts B cell anergy and causes autoimmune disease. , Front. Immunol. , 2023.12. |
| 3. |
Inoue K, Yasuda T, Baba Y, Yamamoto T, Kurosaki T, Shinohara H., Regulation mechanisms of CARMA1–Bcl10–MALT1 complex assembly inferred from the analysis of TRAF6-deficient cells, Genes Cells. , 2023.12. |
| 4. |
Shinya Tanaka, Wataru Ise, Yoshihiro Baba, Tomohiro Kurosaki, Silencing and activating anergic B cells., Immunol Rev, 10.1111/imr.13053., 307, 1, 43-52, 2022.05. |
| 5. |
Shinya Hatano,Keiichiro Mine,Naoto Noguchi,Mitsuru Matsumoto,Yoshihiro Baba,Yasunobu Yoshikai, MHC class II inhibits the generation of IL-17A+ Vγ6 γδ T cells in the thymus at perinatal stage., Eur J Immunol, org/10.1002/eji.202149542, 2022.04. |
| 6. |
Hiroyuki Satofuka, Satoshi Abe, Takashi Moriwaki, Akane Okada, Kanako Kazuki, Hiroshi Tanaka, Kyotaro Yamazaki, Genki Hichiwa, Kayoko Morimoto, Haruka Takayama, Yuji Nakayama, Shinya Hatano, Yutaro Yada, Yasufumi Murakami, Yoshihiro Baba, Mitsuo Oshimura, Kazuma Tomizuka, Yasuhiro Kazuki, Efficient human-like antibody repertoire and hybridoma production in trans-chromosomic mice carrying megabase-sized human immunoglobulin loci., Nat Commun, 10.1038/s41467-022-29421-2., 13, 1, 1841, 2022.04. |
| 7. |
Takayuki Ozawa, Kentaro Fujii 2, Takao Sudo, Yukiko Doi, Ritsuko Nakai, Yasuhiro Shingai, Tomoaki Ueda, Yoshihiro Baba, Naoki Hosen, Takafumi Yokota, Special AT-Rich Sequence-Binding Protein 1 Supports Survival and Maturation of Naive B Cells Stimulated by B Cell Receptors., J Immunol, 10.4049/jimmunol.2101097., 208, 8, 1937-1946, 2022.04. |
| 8. |
Qizhi Liu, Eiji Umemoto, Naoki Morita, Hisako Kayama, Yoshihiro Baba, Tomohiro Kurosaki, Ryu Okumura, Kiyoshi Takeda, Pyruvate enhances oral tolerance via GPR31., Int Immunol, 10.1093/intimm/dxac010., dxac010., 2022.03. |
| 9. |
Kazuhiko Kawata, Akemi Baba, Masayuki Shiota, Hideki Wanibuchi, Yoshihiro Baba, ER membrane protein complex 1 interacts with STIM1 and regulates store-operated Ca2+ entry., J Biochem, J Biochem ., 170, 4, 483-488, 2021.12. |
| 10. |
Tomoharu Yasuda, Yuichi Saito, Chisato Ono, Kazuhiko Kawata, Akemi Baba, Yoshihiro Baba, Generation and characterization of CD19-iCre mice as a tool for efficient and specific conditional gene targeting in B cells., Sci Rep, 10.1038/s41598-021-84786-6., 11, 1, 5524-5524, 2021.03. |
| 11. |
Tanaka S, Ise W, Inoue T, Ito A, Ono C, Shima Y, Sakakibara S, Nakayama M, Fujii K, Miura I, Sharif J, Koseki H, Koni PA, Raman I, Li QZ, Kubo M, Fujiki K, Nakato R, Shirahige K, Araki H, Miura F, Ito T, Kawakami E, Baba Y, Kurosaki T., Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity, Nat Immunol., 10.1038/s41590-020-0700-y., 21, 8, 950-961, 2020.08. |
| 12. |
Taiki Sakaguchi, Ryu Okumura, Chisato Ono, Daisuke Okuzaki, Takafumi Kawai, Yoshifumi Okochi, Natsuko Tanimura, Mari Murakami, Hisako Kayama, Eiji Umemoto, Hidetaka Kioka, Tomohito Ohtani, Yasushi Sakata, Kensuke Miyake, Yasushi Okamura, Yoshihiro Baba, Kiyoshi Takeda, TRPM5 Negatively Regulates Calcium-Dependent Responses in Lipopolysaccharide-Stimulated B Lymphocytes, Cell Rep, 10.1016/j.celrep.2020.107755., 31, 10, 107755-107755, 2020.06. |
| 13. |
Sinya Tanaka, Yoshihiro Baba., B Cell Receptor Signaling., Adv Exp Med Biol, 10.1007/978-981-15-3532-1_2., 1254, 23-36, 2020.04. |
| 14. |
Ryota Usui, Daisuke Yabe, Muhammad Fauzi, Hisanori Goto, Ainur Botagarova, Shinsuke Tokumoto, Hisato Tatsuoka, Yumiko Tahara, Shizuka Kobayashi, Toshiya Manabe, Yoshihiro Baba, Tomohiro Kurosaki, Pedro Luis Herrera, Masahito Ogura, Kazuaki Nagashima, Nobuya Inagaki, GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells, Scientific reports, 10.1038/s41598-019-52048-1, 9, 1, 2019.12, The long-chain fatty acid receptor GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) from pancreatic β-cells. Previous studies demonstrated that GPR40 activation enhances Ca2+ release from the endoplasmic reticulum (ER) by activating inositol 1,4,5-triphosphate (IP3) receptors. However, it remains unknown how ER Ca2+ release via the IP3 receptor is linked to GIIS potentiation. Recently, stromal interaction molecule (STIM) 1 was identified as a key regulator of store-operated Ca2+ entry (SOCE), but little is known about its contribution in GPR40 signaling. We show that GPR40-mediated potentiation of GIIS is abolished by knockdown of IP3 receptor 1 (IP3R1), STIM1 or Ca2+-channel Orai1 in insulin-secreting MIN6 cells. STIM1 and Orai1 knockdown significantly impaired SOCE and the increase of intracellular Ca2+ by the GPR40 agonist, fasiglifam. Furthermore, β-cell-specific STIM1 knockout mice showed impaired fasiglifam-mediated GIIS potentiation not only in isolated islets but also in vivo. These results indicate that the IP3R1/STIM1/Orai1 pathway plays an important role in GPR40-mediated SOCE initiation and GIIS potentiation in pancreatic β-cells.. |
| 15. |
Yoshihiro Baba, Yuichi Saito, Yasuaki Kotetsu, Heterogeneous subsets of B-lineage regulatory cells (Breg cells), International immunology, 10.1093/intimm/dxz068, 32, 3, 155-162, 2019.12, B cells represent a key cellular component of humoral immunity. Besides antigen presentation and antibody production, B cells also play a role in immune regulation and induction of tolerance through several mechanisms. Our understanding of B-lineage cells with regulatory ability has been revolutionized by the delineation of heterogeneous subsets of these cells. Specific environmental signals may further determine the polarization and function of B-lineage regulatory cells. With the availability of new genetic, molecular and pharmacological tools, considerable advances have been made toward our understanding of the surface phenotype, developmental processes and functions of these cells. These exciting discoveries, some of which are still controversial, also raise many new questions, which makes the inhibitory function of B cells a rapidly growing field in immunopathology. Here we review highlights of the regulatory activity of B cells and the recent advances in the function and phenotype of these B-cell subsets in healthy and diseased states.. |
| 16. |
Akiko Nakai, Jun Fujimoto, Haruhiko Miyata, Ralf Stumm, Masashi Narazaki, Stefan Schulz, Yoshihiro Baba, Atsushi Kumanogoh, Kazuhiro Suzuki, The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors, Journal of Experimental Medicine, 10.1084/jem.20181494, 216, 7, 1630-1647, 2019.01, Lymphocyte migration is mediated by G protein–coupled receptors (GPCRs) that respond to chemoattractive molecules. After their activation, GPCRs are phosphorylated by different GPCR kinases (GRKs), which produces distinct functional outcomes through b-arrestins. However, the molecular machinery that targets individual GRKs to activated GPCRs remains elusive. Here, we identified a protein complex consisting of copper metabolism MURR1 domain–containing (COMMD) 3 and COMMD8 (COMMD3/8 complex) as an adaptor that selectively recruits a specific GRK to chemoattractant receptors and promotes lymphocyte chemotaxis. COMMD8, whose stability depended on COMMD3, was recruited to multiple chemoattractant receptors. Deficiency of COMMD8 or COMMD3 impaired B cell migration and humoral immune responses. Using CXC-chemokine receptor 4 (CXCR4) as a model, we demonstrated that the COMMD3/8 complex selectively recruited GRK6 and induced GRK6-mediated phosphorylation of the receptor and activation of b-arrestin–mediated signaling. Thus, the COMMD3/8 complex is a specificity determinant of GRK targeting to GPCRs and represents a point of regulation for immune responses.. |
| 17. |
Yukari Kondo, Shinichiro Higa, Takeshi Iwasaki, Tomoya Matsumoto, Kazumitsu Maehara, Akihito Harada, Yoshihiro Baba, Masatoshi Fujita, Yasuyuki Ohkawa, Sensitive detection of fluorescence in western blotting by merging images, PloS one, 10.1371/journal.pone.0191532, 13, 1, 2018.01, The western blotting technique is widely used to analyze protein expression levels and protein molecular weight. The chemiluminescence method is mainly used for detection due to its high sensitivity and ease of manipulation, but it is unsuitable for detailed analyses because it cannot be used to detect multiple proteins simultaneously. Recently, more attention has been paid to the fluorescence detection method because it is more quantitative and is suitable for the detection of multiple proteins simultaneously. However, fluorescence detection can be limited by poor image resolution and low detection sensitivity. Here, we describe a method to detect fluorescence in western blots using fluorescence microscopy to obtain high-resolution images. In this method, filters and fluorescent dyes are optimized to enhance detection sensitivity to a level similar to that of the chemiluminescence method.. |
| 18. |
Takayoshi Ohba, Hiroyuki Watanabe, Manabu Murakami, Kenji Iino, Takeshi Adachi, Yoshihiro Baba, Tomohiro Kurosaki, Kyoichi Ono, Hiroshi Ito, Stromal interaction molecule 1 haploinsufficiency causes maladaptive response to pressure overload, PloS one, 10.1371/journal.pone.0187950, 12, 11, 2017.11, Stromal interaction molecule 1 (STIM1), an endo/sarcoplasmic reticulum Ca2+ sensor, has been shown to control a Ca2+-dependent signal that promotes cardiac hypertrophy. However, whether STIM1 has adaptive role that helps to protect against cardiac overload stress remains unknown. We hypothesized that STIM1 deficiency causes a maladaptive response to pressure overload stress. We investigated STIM1 heterozygous KO (STIM1+/–) mice hearts, in which STIM1 protein levels decreased to 27% of wild-type (WT) with no compensatory increase in STIM2. Under stress-free conditions, no significant differences were observed in electrocardiographic and echocardiographic parameters or blood pressure between STIM1+/– and WT mice. However, when STIM1+/– mice were subjected to transverse aortic constriction (TAC), STIM1+/– mice had a higher mortality rate than WT mice. The TAC-induced increase in the heart weight to body weight ratio (mean mg/g ± standard error of the mean) was significantly inhibited in STIM1+/– mice (WT sham, 4.12 ± 0.14; WT TAC, 6.23 ± 0.40; STIM1+/– sham, 4.53 ± 0.16; STIM1+/– TAC, 4.63 ± 0.08). Reverse transcription-polymerase chain reaction analysis of the left ventricles of TAC-treated STIM1+/– mice showed inhibited induction of cardiac fetal genes, including those encoding brain and atrial natriuretic proteins. Western blot analysis showed upregulated expression of transient receptor potential channel 1 (TRPC1) in TAC-treated WT mice, but suppressed expression in TAC-treated STIM1+/– mice. Taken together, the hearts of STIM1 haploinsufficient mice had a superficial resemblance to the WT phenotype under stress-free conditions; however, STIM1 haploinsufficient mice showed a maladaptive response to cardiac pressure overload.. |
| 19. |
Naoki Hosen, Yukiko Matsunaga, Kana Hasegawa, Hiroshi Matsuno, Yuki Nakamura, Mio Makita, Kouki Watanabe, Mikako Yoshida, Kei Satoh, Soyoko Morimoto, Fumihiro Fujiki, Hiroko Nakajima, Jun Nakata, Sumiyuki Nishida, Akihiro Tsuboi, Yoshihiro Oka, Masahiro Manabe, Hiroyoshi Ichihara, Yasutaka Aoyama, Atsuko Mugitani, Takafumi Nakao, Masayuki Hino, Ryosuke Uchibori, Keiya Ozawa, Yoshihiro Baba, Seitaro Terakura, Naoki Wada, Eiichi Morii, Junichi Nishimura, Kiyoshi Takeda, Yusuke Oji, Haruo Sugiyama, Junichi Takagi, Atsushi Kumanogoh, The activated conformation of integrin β7 is a novel multiple myeloma-specific target for CAR T cell therapy, Nature medicine, 10.1038/nm.4431, 23, 12, 1436-1443, 2017.01, Cancer-specific cell-surface antigens are ideal targets for monoclonal antibody (mAb)-based immunotherapy but are likely to have previously been identified in transcriptome or proteome analyses. Here, we show that the active conformer of an integrin can serve as a specific therapeutic target for multiple myeloma (MM). We screened >10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb specifically recognizing a subset of integrin β77 molecules. The MMG49 epitope, in the N-terminal region of the β77 chain, is predicted to be inaccessible in the resting integrin conformer but exposed in the active conformation. Elevated expression and constitutive activation of integrin β77 conferred high MMG49 reactivity on MM cells, whereas MMG49 binding was scarcely detectable in other cell types including normal integrin β77 + lymphocytes. T cells transduced with MMG49-derived chimeric antigen receptor (CAR) exerted anti-MM effects without damaging normal hematopoietic cells. Thus, MMG49 CAR T cell therapy is promising for MM, and a receptor protein with a rare but physiologically relevant conformation can serve as a cancer immunotherapy target.. |
| 20. |
Hye Min Lim, Heo Woon, Jung Woo Han, Yoshihiro Baba, Tomohiro Kurosaki, Min Goo Lee, Joo Young Kim, UDP-induced phagocytosis and ATP-stimulated chemotactic migration are impaired in STIM1 -/- microglia in vitro and in vivo, Mediators of Inflammation, 10.1155/2017/8158514, 2017, 2017.01, STIM1 is the only currently known intracellular calcium sensor that functions as the calcium influx regulator controlling immune cell activation. STIM1 function in immune cell calcium signalling has been studied extensively; however, its role in microglia, innate immune cells in brain, has not been fully understood. Here, we report that STIM1-/- murine microglia lost store-operated calcium influx and displayed aberrant immunological functions. Microglial functions regulated by chronic and global Ca2+i changes were reduced significantly, including cytokine releases and opsonin-dependent phagocytosis. More dramatically, cellular functions governed by Ca2+ regulation in local microdomains at the cell periphery, such as UDP-induced phagocytosis and ATP-stimulated chemotactic migration, were severely reduced in STIM1-/- microglia. Interestingly, UDP-induced Orai1 mobilization to the peripheral region was greatly attenuated in STIM1-/- microglia. Their chemotactic migration defect was reproduced in vivo in embryonic brain; the aggregated number of STIM1-/- microglia in LPS- (lipopolysaccharide-) injected lesions was much smaller than that in wild-type microglia. Furthermore, the neuron phagoptosis activities of activated microglia were significantly diminished in the STIM1-/- microglia. These in vitro and in vivo results suggest that STIM1-mediated store-operated calcium entry is important for the regulation of global Ca2+i changes which differentiates into active immune state of microglia, but it is more crucial for the regulation of local [Ca2+] microdomains which mediates the acute motility of murine microglia.. |
| 21. |
Keiko Morimoto, Yoshihiro Baba, Hisaaki Shinohara, Sujin Kang, Satoshi Nojima, Tetsuya Kimura, Daisuke Ito, Yuji Yoshida, Yohei Maeda, Hana Sarashina-Kida, Masayuki Nishide, Takashi Hosokawa, Yasuhiro Kato, Yoshitomo Hayama, Yuhei Kinehara, Tatsusada Okuno, Hyota Takamatsu, Toru Hirano, Yoshihito Shima, Masashi Narazaki, Tomohiro Kurosaki, Toshihiko Toyofuku, Atsushi Kumanogoh, LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation, Scientific reports, 10.1038/srep25738, 6, 2016.05, B-cell receptor (BCR) signaling plays a critical role in B-cell activation and humoral immunity. In this study, we discovered a critical function of leucine-rich repeat kinase 1 (LRRK1) in BCR-mediated immune responses. Lrrk1 mice exhibited altered B1a-cell development and basal immunoglobulin production. In addition, these mice failed to produce IgG3 antibody in response to T cell-independent type 2 antigen due to defects in IgG3 class-switch recombination. Concomitantly, B cells lacking LRRK1 exhibited a profound defect in proliferation and survival upon BCR stimulation, which correlated with impaired BCR-mediated NF-κB activation and reduced expression of NF-κB target genes including Bcl-x L, cyclin D2, and NFATc1/αA. Furthermore, LRRK1 physically interacted and potently synergized with CARMA1 to enhance NF-κB activation. Our results reveal a critical role of LRRK1 in NF-κB signaling in B cells and the humoral immune response.. |
| 22. |
Yusuke Ohmi, Wataru Ise, AkiraHarazono, Daisuke Takakura, Hidehiro Fukuyama, Yoshihiro Baba, Masahi Narazaki, Hirofumi, Shoda, Nobunori Takahashi, Yuki Ohkawa, Shuting Ji, Fumihiro Sugiyama, Keishi Fujio, Atsuhi Kumanogoh, Kazuhiko Yamamoto, Nana Kawasaki, Tomohiro Kurosaki, Yoshimasa Takahashi, Koichi Furukawa., Sialylation converts arthritogenic IgG into inhibitors of collagen-induced arthritis, NATURE COMMUNICATIONS, 10.1038/ncomms11205, 7, 11205, 2016.04. |
| 23. |
Yoshihiro Baba, Barry Ripley, Tadamitsu Kishimoto, Tomohiro Kurosaki, Cytokine Regulation of B Cell Activation and Differentiation, Activation of the Immune System, 10.1016/B978-0-12-374279-7.09017-2, 3, 244-252, 2016.04, The activation and differentiation of B cells are pivotal processes with major implications for host defense and the pathogenesis of immune-mediated diseases. During an immune response, B cells respond to cognate antigen by undergoing massive expansion and class switch recombination during the differentiation of B cells into plasma cells. This differentiation can take place either in follicles where they form germinal centers or in extrafollicular foci. With respect to these responses, B cells are exquisitely regulated by their microenvironment and various factors including cytokines. Cytokines represent a diverse group of soluble mediators that can have multifaceted function. It has been shown that many cytokines act on B cells as B cell growth and differentiation factors. This article focuses on the contribution of cytokines to B cell physiological function, including IL-2, IL-4, IL-10, IL-13, IL-21, IL-35, transforming growth factor γ, and interferons, and discusses their implications for the establishment of humoral immunity. We will also focus on the roles of IL-6 and how these contribute to human diseases.. |
| 24. |
Yoshihiro Baba, Tomohiro Kurosaki, Role of Calcium Signaling in B Cell Activation and Biology, Curr. Top. Microbiol. Immunol., 10.1007/82_2015_477, 393, 143-174, 2015.09. |
| 25. |
Santhanam Shanmughapriya, Sudarsan Rajan, Nicholas E. Hoffman, Xueqian Zhang, Shuchi Guo, Jill E. Kolesar, Kevin J. Hines, Jonathan Ragheb, Neelakshi R. Jog, Roberto Caricchio, Yoshihiro Baba, Yandong Zhou, Brett A. Kaufman, Joseph Y. Cheung, Tomohiro Kurosaki, Donald L. Gill, Muniswamy Madesh, Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU, Science Signaling, 10.1126/scisignal.2005673, 8, 366, ra23, 2015.03, Cytosolic Ca2+ signals, generated through the coordinated translocation of Ca2+ across the plasma membrane (PM) and endoplasmic reticulum (ER) membrane, mediate diverse cellular responses. Mitochondrial Ca2+ is important for mitochondrial function, and when cytosolic Ca2+ concentration becomes too high, mitochondria function as cellular Ca2+ sinks. By measuring mitochondrial Ca2+ currents, we found that mitochondrial Ca2+ uptake was reduced in chicken DT40 B lymphocytes lacking either the ER-localized inositol trisphosphate receptor (IP3R), which releases Ca2+ from the ER, or Orai1 or STIM1, components of the PM-localized Ca2+-permeable channel complex that mediates store-operated calcium entry (SOCE) in response to depletion of ER Ca2+ stores. The abundance of MCU, the pore-forming subunit of the mitochondrial Ca2+ uniporter, was reduced in cells deficient in IP3R, STIM1, or Orai1. Chromatin immunoprecipitation and promoter reporter analyses revealed that the Ca2+-regulated transcription factor CREB (cyclic adenosine monophosphate response element-binding protein) directly bound the MCU promoter and stimulated expression. Lymphocytes deficient in IP3R, STIM1, or Orai1 exhibited altered mitochondrial metabolism, indicating that Ca2+ released from the ER and SOCE-mediated signals modulates mitochondrial function. Thus, our results showed that a transcriptional regulatory circuit involving Ca2+-dependent activation of CREB controls the Ca2+ uptake capability of mitochondria and hence regulates mitochondrial metabolism.. |
| 26. |
Yoshihiro Baba, Masanori Matsumoto, Tomohiro Kurosaki, Signals controlling the development and activity of regulatory B-lineage cells, International Immunology, 10.1093/intimm/dxv027, 27, 10, 487-493, 2015.01, The fundamental concepts surrounding B cells with inhibitory function (regulatory B cells) are now being established. In the context of autoimmune and inflammatory animal models, B cells play an immunomodulatory role via IL-10 production and contribute to limitation of the pathogenesis. Recent studies have notably identified the human counterparts of these cells, which have been suggested to be relevant to the pathophysiology of disease. Clear criteria to identify these cell subsets and the key molecular mechanisms underlying their physiological features are required for understanding the big picture of regulatory B cells. Plasmablasts have recently been identified as a major IL-10-producing regulatory B-cell subset and Ca2+ signaling has furthermore been found to contribute to B-cell IL-10 expression. In this review, the signaling components controlling IL-10-dependent B-cell regulatory function and the development of IL-10-competent/-producing B cells and plasmablasts are discussed.. |
| 27. |
Masanori Matsumoto, Akemi Baba, Takafumi Yokota, Hiroyoshi Nishikawa, Yasuyuki Ohkawa, Hisako Kayama, Axel Kallies, Stephen L Nutt, Shimon Sakaguchi, Kiyoshi Takeda, Tomohiro Kurosaki, Yoshihiro Baba, Interleukin-10-Producing Plasmablasts Exert Regulatory Function in Autoimmune Inflammation, IMMUNITY, 10.1016/j.immuni.2014.10.016, 41, 6, 1040-1051, 2014.12. |
| 28. |
Eunan Hendron, Xizhuo Wang, Yandong Zhou, Xiangyu Cai, Jun-ichi Goto, Katsuhiko Mikoshiba, Yoshihiro Baba, Tomohiro Kurosaki, Youjun Wang, Donald L Gill., Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs, CELL CALCIUM, 10.1016/j.ceca.2014.10.005, 56, 6, 482-492, 2014.12. |
| 29. |
Yoshihiro Baba, Masanori Matsumoto, Tomohiro Kurosaki, Calcium signaling in B cells
Regulation of cytosolic Ca2+ increase and its sensor molecules, STIM1 and STIM2, Molecular Immunology, 10.1016/j.molimm.2013.10.006, 62, 2, 339-343, 2014.12, Calcium signals are crucial for diverse cellular functions including adhesion, differentiation, proliferation, effector functions and gene expression. After engagement of the B cell receptor, the intracellular calcium ion (Ca2+) concentration is increased promoting the activation of various signaling cascades. While elevated Ca2+ in the cytosol initially comes from the endoplasmic reticulum (ER), a continuous influx of extracellular Ca2+ is required to maintain the increased level of cytosolic Ca2+. Store-operated Ca2+ entry manages this process, which is regulated by an ER calcium sensor, stromal interaction molecule (STIM). STIM proteins sense changes in the levels of Ca2+ stored within the ER lumen and regulates the Ca2+-release activated Ca2+ channel in the plasma membrane. This review focuses on the signaling pathways leading to Ca2+ influx and the role of Ca2+ signals in B cell functions.. |
| 30. |
Yukio Furukawa, Shunsuke Teraguchi, Takahisa Ikegami, Onur Dagliyan, Lin Jin, Damien Hall, Nikolay V. Dokholyan, Keiichi Namba, Shizuo Akira, Tomohiro Kurosaki, Yoshihiro Baba, Daron M. Standley, Intrinsic disorder mediates cooperative signal transduction in STIM1, Journal of Molecular Biology, 10.1016/j.jmb.2014.03.006, 426, 10, 2082-2097, 2014.05, Intrinsically disordered domains have been reported to play important roles in signal transduction networks by introducing cooperativity into protein-protein interactions. Unlike intrinsically disordered domains that become ordered upon binding, the EF-SAM domain in the stromal interaction molecule (STIM) 1 is distinct in that it is ordered in the monomeric state and partially unfolded in its oligomeric state, with the population of the two states depending on the local Ca2 + concentration. The oligomerization of STIM1, which triggers extracellular Ca2 + influx, exhibits cooperativity with respect to the local endoplasmic reticulum Ca 2 + concentration. Although the physiological importance of the oligomerization reaction is well established, the mechanism of the observed cooperativity is not known. Here, we examine the response of the STIM1 EF-SAM domain to changes in Ca2 + concentration using mathematical modeling based on in vitro experiments. We find that the EF-SAM domain partially unfolds and dimerizes cooperatively with respect to Ca2 + concentration, with Hill coefficients and half-maximal activation concentrations very close to the values observed in vivo for STIM1 redistribution and extracellular Ca 2 + influx. Our mathematical model of the dimerization reaction agrees quantitatively with our analytical ultracentrifugation-based measurements and previously published free energies of unfolding. A simple interpretation of these results is that Ca2 + loss effectively acts as a denaturant, enabling cooperative dimerization and robust signal transduction. We present a structural model of the Ca2 +-unbound EF-SAM domain that is consistent with a wide range of evidence, including resistance to proteolytic cleavage of the putative dimerization portion.. |
| 31. |
Jana Hartmann, Rosa M. Karl, Ryan P.D. Alexander, Helmuth Adelsberger, Monika S. Brill, Charlotta Rühlmann, Anna Ansel, Kenji Sakimura, Yoshihiro Baba, Tomohiro Kurosaki, Thomas Misgeld, Arthur Konnerth, STIM1 Controls Neuronal Ca2+ Signaling, mGluR1-Dependent Synaptic Transmission, and Cerebellar Motor Behavior, Neuron, 10.1016/j.neuron.2014.03.027, 82, 3, 635-644, 2014.05, In central mammalian neurons, activation of metabotropic glutamate receptor type1 (mGluR1) evokes a complex synaptic response consisting of IP3 receptor-dependent Ca2+ release from internal Ca2+ stores and a slow depolarizing potential involving TRPC3 channels. It is largely unclear how mGluR1 is linked to its downstream effectors. Here, we explored the role of stromal interaction molecule 1 (STIM1) in regulating neuronal Ca2+ signaling and mGluR1-dependent synaptic transmission. By analyzing mouse cerebellar Purkinje neurons, we demonstrate that STIM1 is an essential regulator of the Ca2+ level in neuronal endoplasmic reticulum Ca2+ stores. Both mGluR1-dependent synaptic potentials and IP3 receptor-dependent Ca2+ signals are strongly attenuated in the absence of STIM1. Furthermore, the Purkinje neuron-specific deletion of Stim1 causes impairments in cerebellar motor behavior. Together, our results demonstrate that in the mammalian nervous system STIM1 is a key regulator of intracellular Ca2+ signaling, metabotropic glutamate receptor-dependent synaptic transmission, and motor coordination.. |
| 32. |
Kazunori Masahara, Eiji Umemoto, Hisako Kayama, Manato Kotani, Shota Nakamura, Takashi Kurakawa, Junichi Kikuta, Kazuyoshi Gotoh, Daisuke Motooka, Shintaro Sato, Tomonori Higuchi, Yoshihiro Baba, Tomohiro Kurosaki, Makoto Kinoshita, Youke Shimada, Taishi Kimura, Ryu Okumura, Akira Takeda, Masaru Tajima, Osamu YOshie, Masahiro Fukukazaa, Hiroshi Kiyono, Sidonia Fagarasan, Tetsuya Iida, Masaru Ishii, Kiyoshi Takeda. , Generation of colonic IgA-secreting cells in the caecal patch, NATURE COMMUNICATIONS, 10.1038/ncomms4704, 5, 2014.04. |
| 33. |
Hong Zhang, Regina A. Clemens, Fengchun Liu, Yongmei Hu, Yoshihiro Baba, Pierre Theodore, Tomohiro Kurosaki, Clifford A. Lowell, STIM1 calcium sensor is required for activation of the phagocyte oxidase during in flammation and host defense, Blood, 10.1182/blood-2012-08-450403, 123, 14, 2238-2249, 2014.04, The stromal-interactingmolecule 1 (STIM1) is a potent sensor of intracellular calcium, which in turn regulates entry of external calcium through plasmamembrane channels to affect immune cell activation. Although the contribution of STIM1 to calcium signaling in lymphocytes has been well studied, the role of this protein in neutrophil-mediated inflammation and host defense is unknown. We report that STIM1-deficient murine neutrophils show loss of store-operated calcium entry (SOCE) in response to both soluble ligands that activate G-proteins as well as Fcγ-receptor or integrin ligation that activates tyrosine kinase signaling. This results in modest defects in phagocytosis and degranulation responses but a profound block in superoxide production by the phagocyte oxidase. We trace the primary intracellular target of calcium to be protein kinase C isoforms α and β (PKCα and PKCβ), which in turn phosphorylate subunits of the oxidase leading to superoxide production. In vivo the loss of SOCE in stim1-/- chimeric mice results in marked susceptibility to bacterial infections but also protection from tissue injury in hepatic ischemia/reperfusion injury. These results demonstrate the critical role of STIM1-mediated SOCE and define major protein targets of calcium signaling in neutrophil activation during inflammatory disease.. |
| 34. |
Masanori Matsumoto, Yoshihiro Baba, Role of STIM-dependent Ca2+ influx in regulatory B cells, Yakugaku Zasshi, 10.1248/yakushi.12-00227-2, 133, 4, 419-425, 2013.04, B cells positively regulate immune responses through antibody production and ešector T cell dišerentiation. In addition to such protective roles against pathogenesis, B cells also serve as negative regulators of autoimmunity by secreting an anti-inflammatory cytokine, interleukin-10 (IL-10). These B cell functions are caused by encountering their cognate antigens through their B cell receptors (BCR). A central response of BCR stimulation is intracellular Ca2+ elevation, which is derived mainly from two pathways, Ca2+ release from endoplasmic reticulum (ER) stores and Ca2+ influx from the extracellular space across the plasma membrane. Although a chief Ca2+ entry pathway in immune cells is store-operated Ca2+ (SOC) influx, which is triggered by depletion of Ca2+ from ER, its physiological role in B cells remains elusive. Stromal interaction molecules (STIM), which consist of STIM1 and its homolog, STIM2, serve as ER calcium sensors and are essential for SOC influx after antigen stimulation. We have recently found that STIM1- and STIM2-in-duced SOC influx is critical for regulatory B cell function required to limit experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Even through several B cell populations have been reported to suppress inflammation of autoimmune diseases through production of IL-10, which subset of them exerts their regulatory function during EAE is not fully understood. This review focuses on our recent progress in the role of STIM-dependent SOC influx as a key signal for B cell regulatory function and the latest & findings for understanding how regulatory B cells suppress the development of EAE.. |
| 35. |
Yoko Fujii, Masayuki Shiota, Yasuyuki Ohkawa, Akemi Baba, Hideki Wanibuchi, Tatsuo Kinashi, Tomohiro Kurosaki, Yoshihiro Baba, Surf4 modulates STIM1-dependent calcium entry, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 10.1016/j.bbrc.2012.05.037, 422, 4, 615-620, 2012.06. |
| 36. |
Yoshihiro Baba, Tomohiro Kurosaki, Impact of Ca2+ signaling on B cell function, Trends in Immunology, 10.1016/j.it.2011.09.004, 32, 12, 589-594, 2011.12, In B cells, changes in intracellular concentration of Ca2+ drive signal transduction to initiate changes in gene expression and various cellular events, including apoptosis and differentiation. B cell receptor engagement causes a transient Ca2+ flux from the endoplasmic reticulum Ca2+ store, followed by a continuous increase in intracellular Ca2+ concentration, mainly resulting from store-operated Ca2+ entry (SOCE). The recent identification of stromal interaction molecule (STIM) and Orai as essential components for SOCE has allowed researchers to probe further the role of Ca2+ signals in B cell biology. Here, we summarize the B cell signaling pathways that lead to SOCE, the role of Ca2+ signals in B cell regulatory function, and how a breakdown in the balance of Ca2+ signals is associated with immune-related disease.. |
| 37. |
Masanori Matsumoto, Yoko Fujii, Akemi Baba, Masaki Hikida, Tomohiro Kurosaki, Yoshihiro Baba, The Calcium Sensors STIM1 and STIM2 Control B Cell Regulatory Function through Interleukin-10 Production, Immunity, 10.1016/j.immuni.2011.03.016, 34, 5, 703-714, 2011.05, A chief Ca2+ entry pathway in immune cells is store-operated Ca2+ (SOC) influx, which is triggered by depletion of Ca2+ from the endoplasmic reticulum (ER). However, its physiological role in B cells remains elusive. Here, we show that ER calcium sensors STIM1- and STIM2-induced SOC influx is critical for B cell regulatory function. B cell-specific deletion of STIM1 and STIM2 in mice caused a profound defect in B cell receptor (BCR)-induced SOC influx and proliferation. However, B cell development and antibody responses were unaffected. Remarkably, B cells lacking both STIM proteins failed to produce the anti-inflammatory cytokine IL-10 because of defective activation of nuclear factor of activated T cells (NFAT) after BCR stimulation. This resulted in exacerbation of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our data establish STIM-dependent SOC influx as a key signal for B cell regulatory function required to limit autoimmunity.. |
| 38. |
Kurosaki T, Yoshihiro Baba, Ca2+ signaling and STIM1, PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY, 10.1016/j.pbiomolbio.2010.02.004, 103, 1, 51-58, 2010.09. |
| 39. |
Brian J Hawkinds, Krishna M Irrinki, Karthik Mallilankaraman, Yu-Chin Lien, Youjun Wang, Cunnigaiper D Bhanumathy, Ramasamy Subbiah, Michael F Ritchie, Jonathan Soboloff, Yoshihiro Baba, Tomohiro Kurosaki, Suresh K Joseph, Donald L Gill, Muniswamy Madesh., S-glutathionylation activates STIM1 and alters mitochondrial homeostasis, JOURNAL OF CELL BIOLOGY, 10.1083/jcb.201004152, 190, 3, 391-405, 2010.08. |
| 40. |
Tomohiro Kurosaki, Hisaaki Shinohara, Yoshihiro Baba, B cell signaling and fate decision, Annual Review of Immunology, 10.1146/annurev.immunol.021908.132541, 28, 21-55, 2010.04, Antigen receptors on the surface of B lymphocytes trigger adaptive immune responses after encountering their cognate antigens but also control a series of antigen-independent checkpoints during B cell development. These physiological processes are regulated by the expression and function of cell surface receptors, intracellular signaling molecules, and transcription factors. The function of these proteins can be altered by a dynamic array of post-translational modifications, using two interconnected mechanisms. These modifications can directly induce an altered conformational state in the protein target of the modification itself. In addition, they can create new binding sites for other protein partners, thereby contributing to where and when such multiple protein assemblies are activated within cells. As a new type of post-transcriptional regulator, microRNAs have emerged to luence the development and function of B cells by affecting the expression of target mRNAs.. |
| 41. |
Takao Morita, Akihiko Tanimura, Yoshihiro Baba, Tomohiro Kurosaki, Yosuke Tojyo, A novel stim1-dependent, non-capacitative Ca2+ entry pathway is activated by B cell receptor stimulation and depletion of Ca2+ stores, Journal of Medical Investigation, 10.2152/jmi.56.383, 56, SUPPL. 1, 383-387, 2009.12, In most non-excitable cells, the depletion of intracellular Ca2+ stores activates capacitative Ca2+ entry (CCE), which is a Ca 2+-selective and La3+-sensitive entry pathway. Here, we report a novel mechanism of La3+-resistant Ca2+ entry that is synergistically regulated by B cell receptor (BCR) stimulation and Ca 2+ store depletion (B-SOC). In the wildtype (WT) DT40 cells, BCR stimulation with anti-IgM antibodies induced Ca2+ release and subsequent Ca2+ entry in the presence of 0.3 μMLa3+ which blocks CCE completely. In the inositol 1,4,5-trisphosphate receptor-deficient (IP3R-KO) cells, BCR stimulation elicited neither Ca2+ release nor Ca2+ entry. However, under pretreatment of thapsigargin (ThG), BCR stimulation induced La3+-resistant Ca 2+ entry into both WT and IP3R-KO cells. These results indicate that BCR stimulation and Ca2+ store depletion work in concert to activate the La3+-resistant Ca2+ entry pathway. B-SOC was inhibited by tyrosine kinase inhibitor, genistein. In addition, B-SOC was completely abolished in Stim1-deficient cells and was restored by overexpression of yellow fluorescent protein (YFP)-tagged Stim1, but was unaffected by double knockdown of Orai1/Orai2. These results demonstrate a unique non-CCE pathway, in which Ca2+ entry depends on Stim1 and tyrosine kinase activation. It is likely that similar regulation of Ca2+ entry occurs in other cell types including salivary gland cells.. |
| 42. |
Yoshihiro Baba, Tomohiro Kurosaki, Physiological function and molecular basis of STIM1-mediated calcium entry in immune cells, Immunological Reviews, 10.1111/j.1600-065X.2009.00813.x, 231, 1, 174-188, 2009.09, Calcium signals in immune cells regulate a variety of physiological responses such as cell activation, differentiation, gene transcription, and effector functions. Surface receptor stimulation induces an increase in the concentration of cytosolic calcium ions (Ca2+), which are derived mainly from two sources, intracellular endoplasmic reticulum (ER) Ca 2+ stores and the extracellular space. The major cascade for Ca 2+ entry in immune cells is through store-operated Ca2+ entry (SOCE) and Ca2+ release-activated Ca2+ (CRAC) channels. Activation of SOCE is triggered by depletion of intracellular ER Ca2+ stores, but the molecular mechanism was a long-standing issue. With the recent molecular identification of the ER Ca2+ sensor [stromal interacting molecule-1 (STIM1)] and a pore-forming subunit of the CRAC channel (Orai1), our understanding of the SOCE activation pathway has increased dramatically. These advances have now made it possible to shed some light on important questions: what is the physiological significance of SOCE, and what is its molecular basis? This review focuses on the recent progress in the field and the exciting opportunities for understanding how SOCE influences diverse immune functions.. |
| 43. |
Youjun Wang, Xiaoxiang Deng, Yandong Zhou, Eunan Hendron, Salvatore Mancarella, Michael F. Ritchie, Xiang D. Tang, Yoshihiro Baba, Tomohiro Kurosaki, Yasuo Mori, Jonathan Soboloff, Donald L. Gill, STIM protein coupling in the activation of Orai channels, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.0900293106, 106, 18, 7391-7396, 2009.05, STIM proteins are sensors of endoplasmic reticulum (ER) luminal Ca 2+ changes and rapidly translocate into near plasma membrane (PM) junctions to activate Ca 2+ entry through the Orai family of highly Ca 2+-selective "store-operated" channels (SOCs). Dissecting the STIM-Orai coupling process is restricted by the abstruse nature of the ER-PM junctional domain. To overcome this problem, we studied coupling by using STIM chimera and cytoplasmic C-terminal domains of STIM1 and STIM2 (S1ct and S2ct) and identifying a fundamental action of the powerful SOC modifier, 2-aminoethoxy- diphenyl borate (2-APB), the mechanism of which has eluded recent scrutiny. We reveal that 2-APB induces profound, rapid, and direct interactions between S1ct or S2ct and Orai1, effecting full Ca 2+ release-activated Ca 2+ (CRAC) current activation. The short 235-505 S1ct coiled-coil region was sufficient for functional Orail coupling. YFP-tagged S1ct or S2ct fragments cleared from the cytosol seconds after 2-APB addition, binding avidly to Orai1-CFP with a rapid increase in FRET and transiently increasing CRAC current 200-fold above basal levels. Functional S1ct-Orai1 coupling occurred in STIM1/STIM2-/" DT40 chicken B cells, indicating ct fragments operate independently of native STIM proteins. The 2-APB-induced S1ct-Orai1 and S2-ct-Orai1 complexes undergo rapid reorganization into discrete colocalized PM clusters, which remain stable for >100 s, well beyond CRAC activation and subsequent deactivation. In addition to defining 2-APB's action, the locked STIMct-Orai complex provides a potentially useful probe to structurally examine coupling.. |
| 44. |
Takao Morita, Akihiro Tanimura, Yoshihiro Baba, Tomohiro Kurosaki, Yosuke Tojyo, A Stim1-dependent, noncapacitative Ca2+-entry pathway is activated by B-cell-receptor stimulation and depletion of Ca2+, Journal of Cell Science, 10.1242/jcs.041640, 122, 8, 1220-1228, 2009.04, The depletion of intracellular Ca2+ stores activates capacitative Ca2+ entry (CCE), which is a Ca2+-selective and La3+-sensitive entry pathway. Here, we report a novel mechanism of La3+-resistant Ca2+ entry that is synergistically regulated by B-cell-receptor (BCR) stimulation and Ca2+ store depletion. In DT40 cells, stimulation of BCRs with anti-IgM antibodies induced Ca2+ release and subsequent Ca2+ entry in the presence of 0.3 μM La3+, a condition in which CCE is completely blocked. This phenomenon was not observed in inositol 1,4,5-trisphosphate receptor-deficient DT40 (IP3R-KO) cells. However, in response to thapsigargin pretreatment, BCR stimulation induced La3+- resistant Ca2+ entry into both wild-type and IP3R-KO cells. These results indicate that BCR stimulation alone does not activate Ca2+ entry, whereas BCR stimulation and depleted Ca2+ stores (either due to IP3R-mediated Ca2+ release or Ca2+ uptake inhibition) work in concert to activate La3+-resistant Ca2+ entry. This Ca2+ entry was inhibited by genistein. In addition, BCR-mediated Ca2+ entry was completely abolished in Stim1-deficient DT40 cells and was restored by overexpression of YFP-Stim1, but was unaffected by double knockdown of Orai1 and Orai2. These results demonstrate a unique non-CCE pathway, in which Ca2+ entry depends on Stim1- and BCR-mediated activation of tyrosine kinases.. |
| 45. |
Sachin Malhotra, Yoshihiro Baba, Karla P. Garrett, Frank J.T. Staal, Rachel Gerstein, Paul W. Kincade, Contrasting responses of lymphoid progenitors to canonical and noncanonical Wnt signals, Journal of Immunology, 10.4049/jimmunol.181.6.3955, 181, 6, 3955-3964, 2008.09, The Wnt family of secreted glycoproteins has been implicated in many aspects of development, but its contribution to blood cell formation is controversial. We overexpressed Wnt3a, Wnt5a, and Dickkopf 1 in stromal cells from osteopetrotic mice and used them in coculture experiments with highly enriched stem and progenitor cells. The objective was to learn whether and how particular stages of B lymphopoiesis are responsive to these Wnt family ligands. We found that canonical Wnt signaling, through Wnt3a, inhibited B and plasmacytoid dendritic cell, but not conventional dendritic cell development. Wnt5a, which can oppose canonical signaling or act through a different pathway, increased B lymphopoiesis. Responsiveness to both Wnt ligands diminished with time in culture and stage of development. That is, only hematopoietic stem cells and very primitive progenitors were affected. Although Wnt3a promoted retention of hematopoietic stem cell markers, cell yields and dye dilution experiments indicated it was not a growth stimulus. Other results suggest that lineage instability results from canonical Wnt signaling. Lymphoid progenitors rapidly down-regulated RAG-1, and some acquired stem cell-staining characteristics as well as myeloid and erythroid potential when exposed to Wnt3a-producing stromal cells. We conclude that at least two Wnt ligands can differentially regulate early events in B lymphopoiesis, affecting entry and progression in distinct differentiation lineages.. |
| 46. |
Yoshihiro Baba, Keigo Nishida, Yoko Fujii, Toshio Hirano, Masaki Hikida, Tomohiro Kurosaki., Essential function for the calcium sensor STIM1 in mast cell activation and anaphylactic responses, NATURE IMMUNOLOGY, 10.1038/ni1546, 9, 1, 81-88, 2008.01. |
| 47. |
Yoshihiro Baba, Tomohiro Kurosaki, Regulation of store-operated calcium entry by STIM1, Seikagaku, 80, 12, 1123-1128, 2008. |
| 48. |
Yoshihiro Baba, Kenji Hayashi, Yoko Fujii, Akiko Mizushima, Hiroshi Watarai, Minoru Wakamori, Takuro Numaga, Yasuo Mori, Masamitsu Iino, Masaki Hikida, Tomohiro Kurosaki., Coupling of STIM1 to store-operated Ca2+ entry through its constitutive and inducible movement in the endoplasmic reticulum, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 10.1073/pnas.0608358103, 103, 45, 16704-16709, 2006.11. |
| 49. |
Yoshihiro Baba, Takafumi Yokota, Hergen Spits, Karla P. Garrett, Shin Ichi Hayashi, Paul W. Kincade, Constitutively active β-catenin promotes expansion of multipotent hematopoietic progenitors in culture, Journal of Immunology, 177, 4, 2294-2303, 2006.08, This study was designed to investigate one component of the Wnt/β-catenin signaling pathway that has been implicated in stem cell self-renewal. Retroviral-mediated introduction of stable β-catenin to primitive murine bone marrow cells allowed the expansion of multipotential c-KitlowSca-1low/-CD19- CD11b/Mac-1 -Flk-2-CD43+AA4.1 +NK1.1+CD3-CD11c-Gr-1 -CD45R/B220+ cells in the presence of stromal cells and cytokines. They generated myeloid, T, and B lineage lymphoid cells in culture, but had no T lymphopoietic potential when transplanted. Stem cell factor and IL-6 were found to be minimal requirements for long-term, stromal-free propagation, and a β-catenin-transduced cell line was maintained for 5 mo with these denned conditions. Although multipotential and responsive to many normal stimuli in culture, it was unable to engraft several types of irradiated recipients. These findings support previous studies that have implicated the canonical Wnt pathway signaling in regulation of multipotent progenitors. In addition, we demonstrate how it may be experimentally manipulated to generate valuable cell lines.. |
| 50. |
Hideya Igarashi, Yoshihiro Baba, Yoshinori Nagai, Eijiro Jimi, Sankar Ghosh, Paul W. Kincade, NF-κB is dispensable for normal lymphocyte development in bone marrow but required for protection of progenitors from TNFα, International Immunology, 10.1093/intimm/dxl002, 18, 5, 653-659, 2006.05, Levels of the nuclear factor-kappa B (NF-κB)/Rel family of proteins are carefully modulated in differentiating lymphocytes, where these transcription factors are thought to be important for survival and fate decisions. In contrast, gene-targeting experiments have not revealed clear roles for these transcription factors in lymphopoiesis within bone marrow. Inhibition of NF-κB by introduction of mutated IκBα, a 'superinhibitor' of NF-κB, into hematopoietic stem cells or early progenitors suppressed B as well as T lymphopoiesis following transplantation into immunodeficient mice. Furthermore, a NF-κB essential modifier-binding domain (NBD) peptide that blocks IKB kinase (IKK) activity selectively impaired the generation of adult B lineage cells. However, this suppression did not occur when a neutralizing antibody to tumor necrosis factor α (TNFα) was added to the cultures, or in circumstances where few non-lymphoid cells were present. We conclude that while NF-κB plays a survival-promoting role in lymphoid progenitors, this may only be significant in circumstances such as transplantation when levels of TNFα are high.. |
| 51. |
Yoshihiro Baba, Karla P Garrett, Paul W Kincade., Constitutively active beta-catenin confers multilineage differentiation potential on lymphoid and myeloid progenitors, IMMUNITY, 10.1016/j.immuni.2005.10.009, 23, 6, 599-609, 2005.12. |
| 52. |
Kazuhiko Maeda, Yoshihiro Baba, Yoshinori Nagai, Kozo Miyazaki, Alexander Malykhin, Koji Nakamura, Paul W Kincad, Nobuo Sakaguchi, K Mark Coggeshall., IL-6 blocks a discrete early step in lymphopoiesis, BLOOD, 10.1182/blood-2005-02-0456, 106, 3, 879-885, 2005.08. |
| 53. |
Rosana Pelayo, Rob Welner, S Scott Perry, Jiaxue Huang, Yoshihiro Baba, Takafumi Yokota, Paul W Kincade, Lymphoid progenitors and primary routes to becoming cells of the immune system, CURRENT OPINION IN IMMUNOLOGY, 10.1016/j.coi.2005.01.012, 17, 2, 100-107, 2005.04. |
| 54. |
Yoshihiro Baba, Rosana Pelayo, Paul W Kincade., Relationships between hematopoietic stem cells and lymphocyte progenitors, TRENDS IN IMMUNOLOGY, 10.1016/j.it.2004.09.010, 25, 12, 645-649, 2004.12. |
| 55. |
M. Kawakami, T. Kimura, Y. Kishimoto, T. Tatekawa, Y. Baba, T. Nishizaki, N. Matsuzaki, Y. Taniguchi, S. Yoshihara, K. Ikegame, T. Shirakata, S. Nishida, T. Masada, N. Hosen, A. Tsuboi, Y Oji, Y. Oka, H. Ogawa, Y. Sonoda, H. Sugiyama, I. Kawase, T. Soma., Preferential expression of the vasoactive intestinal peptide (VIP) receptor VPAC1 in human cord blood-derived CD34(+)CD38(-) cells: possible role of VIP as a growth-promoting factor for hematopoietic stem/progenitor cells, LEUKEMIA, 10.1038/sj.leu.2403330, 18, 5, 912-921, 2004.05. |
| 56. |
Dai Watanabe, Shoji Hashimoto, Masamichi Ishiai, Masato Matsushita, Yoshihiro Baba, Tadamitsu Kishimoto, Tomohiro Kurosaki, Satoshi Tsukada, Four Tyrosine Residues in Phospholipase C-γ2, Identified as Btk-dependent Phosphorylation Sites, Are Required for B Cell Antigen Receptor-coupled Calcium Signaling, Journal of Biological Chemistry, 10.1074/jbc.M103675200, 276, 42, 38595-38601, 2001.10, Activation of phospholipase C-γ2 (PLCγ2) is the critical step in B cell antigen receptor (BCR)-coupled calcium signaling. Although genetic dissection experiments on B cells have demonstrated that Bruton's tyrosine kinase (Btk) and Syk are required for activating PLCγ2, the exact activation mechanism of PLCγ2 by these kinases has not been established. We identify the tyrosine residues 753, 759, 1197 and 1217 in rat PLCγ2 as Btk-dependent phosphorylation sites by using an in vitro kinase assay. To evaluate the role of these tyrosine residues in phosphorylation-dependent activation of PLCγ2, PLCγ2-deficient DT40 cells were reconstituted with a series of mutant PLCγ2s in which the phenylalanine was substituted for tyrosine. Substitution of all four tyrosine residues almost completely eliminated the BCR-induced PLCγ2 phosphorylation, indicating that these residues include the major phosphorylation sites upon BCR engagement. Cells expressing PLCγ2 with a single substitution exhibited some extent of reduction in calcium mobilization, whereas those expressing quadruple mutant PLCγ2 showed greatly reduced calcium response. These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as Btk-dependent phosphorylation sites in vitro, coordinately contribute to BCR-induced activation of PLCγ2.. |
| 57. |
Takeshi Futatani, Chiaki Watanabe, Yoshihiro Baba, Satoshi Tsukada, Hans D. Ochs, Bruton's tyrosine kinase is present in normal platelets and its absence identifies patients with X-linked agammaglobulinaemia and carrier females, British Journal of Haematology, 10.1046/j.1365-2141.2001.02905.x, 114, 1, 141-149, 2001.08, X-linked agammaglobulinaemia (XLA) is a primary immunodeficiency caused by mutations in the gene coding for Bruton's tyrosine kinase (Btk) and is characterized by an arrest of B-cell development. We analysed Btk protein expression in platelets using flow cytometry and found that normal platelets express large amounts of Btk. Assessment of affected males from 45 unrelated XLA families revealed that platelets of the majority of the patients (37 out of 45 families) had decreased or absent Btk expression, and that platelets from carrier females of these families had both normal and mutated Btk expression, indicating that megakaryocytes in XLA carriers undergo random X-chromosome inactivation. These observations demonstrate that Btk is not crucial for maturation of megakaryocytes and the production of platelets. No correlation between Btk expression in platelets and clinical phenotype was observed in this study. Flow cytometric evaluation using platelets is a simple and rapid method to test Btk expression. It may be used as a screening test for XLA and for carrier detection, followed, if necessary, by more expensive mutation analyses.. |
| 58. |
Yoshihiro Baba, Shoji Hashimoto, Masato Matsushita, Dai Watanabe, Tadamitsu Kishimoto, Tomohiro Kurosaki, Satoshi Tsukada, BLNK mediates Syk-dependent Btk activation, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.051626198, 98, 5, 2582-2586, 2001.02, Btk is a critical molecule in B cell antigen receptor (BCR)-coupled signaling, and its activity is regulated by Lyn and Syk. Although the molecular mechanism of Lyn-dependent Btk activation has been investigated, that of Syk-dependent Btk activation has remained unidentified. We have demonstrated that BLNK mediates Syk-dependent Btk activation. In a reconstitution cell system, coexpression of BLNK allows Syk to phosphorylate Btk on its tyrosine 551, leading to the enhancement of Btk activity. This phosphorylation depends on the interaction of Btk and BLNK by means of the Btk-Src homology 2 domain. The existence of such an activation mechanism is supported by the observation that the BCR-induced Btk phosphorylation and activation are significantly reduced in BLNK-deficient B cells as well as in Syk-deficient B cells. Although previous observations have identified the function of BLNK as the linker that integrates the action of Btk and Syk into downstream effectors such as phospholipase Cγ2, our present study indicates another function of BLNK that connects the activity of Syk to that of Btk.. |
| 59. |
Satoshi Tsukada, Yoshihiro Baba, Dai Watanabe, Btk and BLNK in B cell development, Advances in Immunology, 10.1016/S0065-2776(01)77016-2, 77, 123-162, 2001.01. |
| 60. |
Yoshihiro Baba, M. Matsushita, Y. Matsuda, J. Inazawa, T. Yamadori, S. Hashimoto, T. Kishimoto, Satoshi Tsukada, Assignment of SH3BP5/Sh3bp5 encoding Sab, an SH3 domain-binding protein which preferentially associates with Bruton's tyrosine kinase, to human chromosome 1q43 and mouse chromosome 14B by in situ hybridization, Cytogenetics and Cell Genetics, 87, 3-4, 221-222, 1999.12. |
| 61. |
Shoji Hashimoto, Akihiro Iwamatsu, Masamichi Ishiai, Katsuya Okawa, Tomoki Yamadori, Masato Matsushita, Yoshihiro Baba, Tadamitsu Kishimoto, Tomohiro Kurosaki, Satoshi Tsukada, Identification of the SH2 domain binding protein of Bruton's tyrosine kinase as BLNK - Functional significance of Btk-SH2 domain in B-cell antigen receptor-coupled calcium signaling, Blood, 94, 7, 2357-2364, 1999.10, Bruton's tyrosine kinase (Btk) is a critical component in the B-cell antigen receptor (BCR)-coupled signaling pathway. Its deficiency in B cells leads to loss or marked reduction in the BCR-induced calcium signaling. It is known that this BCR-induced calcium signaling depends on the activation of phospholipase Cγ (PLCγ), which is mediated by Btk and another tyrosine kinase Syk and that the SH2 and pleckstrin homology (PH) domains of Btk play important roles in this activation process. Although the importance of the PH domain of Btk has been explained by its role in the membrane targeting of Btk, the functional significance of the SH2 domain in the calcium signaling has remained merely a matter of speculation. In this report, we identify that one of the major Btk-SH2 domain-binding proteins in B cells is BLNK (B-cell linker protein) and present evidences that the interaction of BLNK and the SH2 domain of Btk contributes to the complete tyrosine phosphorylation of PLCγ.. |
| 62. |
Tomoki Yamadori, Yoshihiro Baba, Masato Matsushita, Shoji Hashimoto, Mari Kurosaki, Tomohiro Kurosaki, Tadamitsu Kishimoto, Satoshi Tsukada, Bruton's tyrosine kinase activity is negatively regulated by Sab, the Btk-SH3 domain-binding protein, Proceedings of the National Academy of Sciences of the United States of America, 10.1073/pnas.96.11.6341, 96, 11, 6341-6346, 1999.05, Bruton's tyrosine kinase (Btk) is a cytoplasmic tyrosine kinase that is crucial for human and murine B cell development, and its deficiency causes human X-linked agammaglobulinemia and murine X-linked immunodeficiency. In this report, we describe the function of the Btk-binding protein Sab (SH3- domain binding protein that preferentially associates with Btk), which we reported previously as a newly identified Src homology 3 domain-binding protein. Sab was shown to inhibit the auto- and transphosphorylation activity of Btk, which prompted us to propose that Sab functions as a transregulator of Btk. Forced overexpression of Sab in B cells led to the reduction of B cell antigen receptor-induced tyrosine phosphorylation of Btk and significantly reduced both early and late B cell antigen receptor-mediated events, including calcium mobilization, inositol 1,4,5-trisphosphate production, and apoptotic cell death, where the involvement of Btk activity has been demonstrated previously. Together, these results indicate the negative regulatory role of Sab in the B cell cytoplasmic tyrosine kinase pathway.. |
| 63. |
Yoshihiro Baba, Shigeaki Nonoyama, Masato Matsushita, Tomoki Yamadori, Shoji Hashimoto, Kohsuke Imai, Shigeyuki Arai, Toshio Kunikata, Masashi Kurimoto, Tomohiro Kurosaki, Hans D. Ochs, Jun Ichi Yata, Tadamitsu Kishimoto, Satoshi Tsukada, Involvement of Wiskott-Aldrich syndrome protein in B-cell cytoplasmic tyrosine kinase pathway, Blood, 93, 6, 2003-2012, 1999.03, Bruton's tyrosine kinase (Btk) has been shown to play a role in normal B-lymphocyte development. Defective expression of Btk leads to human and murine immunodeficiencies. However, the exact role of Btk in the cytoplasmic signal transduction in B cells is still unclear. This study represents a search for the substrate for Btk in vivo. We identified one of the major phosphoproteins associated with Btk in the preB cell line NALM6 as the Wiskott-Aldrich syndrome protein (WASP), the gene product responsible for Wiskott-Aldrich syndrome, which is another hereditary immunodeficiency with distinct abnormalities in hematopoietic cells. We demonstrated that WASP was transiently tyrosine-phosphorylated after B-cell antigen receptor cross- linking on B cells, suggesting that WASP is located downstream of cytoplasmic tyrosine kinases. An in vivo reconstitution system demonstrated that WASP is physically associated with Btk and can serve as the substrate for Btk. A protein binding assay suggested that the tyrosine-phosphorylation of WASP alters the association between WASP and a cellular protein. Furthermore, identification of the phosphorylation site of WASP in reconstituted cells allowed us to evaluate the catalytic specificity of Btk, the exact nature of which is still unknown.. |
| 64. |
C. Watanabe, T. Futatani, Yoshihiro Baba, S. Tsukada, A. Oda, H. D. Ochs, Bruton's Tyrosine Kinase (BTK) is present in normal platelets, and its absence identifies patients with X-Linked Agammaglobulinemia (XLA) and carrier females, Journal of Investigative Medicine, 47, 2, 1999, Platelets contain substantial amounts of Btk that can be readily demonstrated by staining permeabilized platelets with monoclonal antibody 48-2H followed by flow cytometry. To test the usefulness of this technique for establishing the diagnosis of XLA and to identify carrier females, we quantified Btk by staining platelets from normal controls, XLA patients with known Btk mutations, and female relatives of XLA patients with ascertained carrier status. Platelets isolated from fresh or up-to-two-day-old citrated blood were permeabilized with Saponin, incubated with mAb 48-2H, and staining intensity measured by flow cytometry. The staining patterns observed identified affected boys and carrier females in 12 of 14 XLA families studied. In eight families, patient platelets failed to bind mAb 48-2H (A) and carrier platelets showed two distinct peaks (D); in four families the mAb binding by XLA platelets was decreased (B) and carrier females showed two peaks forming a shoulder (E); two families showed a normal pattern (C, F). These results suggest that the majority (∼ 85%) of Btk mutations observed in XLA families result in the absence of Btk or in a mutated protein that is poorly recognized by mAb 48-2H, and that megakaryocytes from female carriers for XLA undergo random X-inactivation. (Graph Presented).. |
| 65. |
Masato Matsushita, Tomoki Yamadori, Seishi Kato, Yoshihiro Takemoto, Jouji Inazawa, Yoshihiro Baba, Shoji Hashimoto, Shingo Sekine, Shigeyuki Arai, Toshio Kunikata, Masashi Kurimoto, Tadamitsu Kishimoto, Satoshi Tsukada, Identification and characterization of a novel SH3-domain binding protein, Sab, which preferentially associates with Bruton's tyrosine kinase (Btk), Biochemical and Biophysical Research Communications, 10.1006/bbrc.1998.8420, 245, 2, 337-343, 1998.04, Protein interaction cloning method was used to identify a novel molecule, Sab, which binds to the SH3 domain of Bruton's tyrosine kinase (Btk), the deficient cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia and murine X-linked immunodeficiency. Immunoprecipitation using the anti-Sab antibody identified the protein product of the gene as a 70 kDa molecule. While Sab does not have a proline-rich sequence, it was shown to bind to Btk through the commonly conserved structure among SH3 domains. Remarkably, Sab exhibited a high preference for binding to Btk rather than to other cytoplasmic tyrosine kinases, which suggests a unique role of Sab in the Btk signal transduction pathway.. |
| 66. |
Yoshihiro Baba, S. Nonoyama, K. Imai, H. D. Ochs, J. Yata, T. Kishimoto, Involvement of Wiskott-Aldrich Syndrome Protein (WASP) in B cell antigen receptor and Btk signaling pathway, FASEB Journal, 12, 5, 1998.03, Bruton's tyrosine kinase (Btk) is a cytoplasmic tyrosine kinase which is involved in the pathogenesis of human and murine B cell deficiencies. In this study, we attempted to identify the downstream molecule in the Btk signaling pathway. We showed that WASP physically associated with Btk in B-lineage cells and was constitutively phosphorylated on its tyrosine in a preB cell line in which the tyrosine-phosphorylation of Btk was also prominent WASP was shown to be phosphorylated by Btk in cotransfection system. The phosphotyrosine motif of WASP was distinctly similar to that of the autophosphorylation site of Btk. Furthermore, WASP was shown to be tyrosine-phosphorylated upon B cell antigen receptor crosslinking. These results indicate a physical and functional link of Btk and WASP, and also suggest a possible involvement of WASP in the antigen receptor signaling pathway in B-lineage cells together with Btk.. |
| 67. |
Junji Sagara, Tadafumi S. Tochikura, Hajime Tanaka, Yoshihiro Baba, Shoichiro Tsukita, Sachiko Tsukita, Akihiko Kawai, The 21-kDa polypeptide (VAP21) in the rabies virion is a CD99-related host cell protein, MICROBIOLOGY and IMMUNOLOGY, 10.1111/j.1348-0421.1998.tb02285.x, 42, 4, 289-297, 1998.01, In our monoclonal antibody (MAb) stocks prepared against the BHK-21 cell antigens, two (11875 and 28276) recognized a 21-kDa polypeptide (referred to as VAP21) which is efficiently incorporated into the rabies virion. By using these MAbs, we isolated the cDNA clones that encoded a polypeptide of 144 amino acids from our BHK-21 cell cDNA library. Based on the following evidence, the cDNA was assumed to encode a full-length sequence of VAP21 antigen: i) expression of the eDNA in animal cells resulted in the production of a polypeptide recognized by the two MAbs, and its electrophoretic mobility was the same as that of authentic VAP21 antigen; and ii) immunization with the products from the cDNA-transformed E. coli cells raised specific antibodies in rabbits that recognized a 21-kDa polypeptide in the virion. From the deduced amino acid sequence, it is suggested that the VAP21 antigen has a molecular structure of type-I transmembrane protein containing characteristic proline-rich and glycine-rich regions in its ectodomain. Homology searches resulted in finding homologous sequences (totally about 40 % homology) in the human MIC2 gene product (CD99; 32-kDa) of T lymphocytes. These results suggest that the VAP21 antigen in the rabies virion is a cellular CD99-related transmembrane protein.. |
