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Tomohiro Kurosaki - One of the best experts on this subject based on the ideXlab platform.
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phospholipase c γ2 and vav cooperate within signaling microclusters to propagate b cell spreading in response to membrane bound antigen
Journal of Experimental Medicine, 2008Co-Authors: Michele Weber, Tomohiro Kurosaki, Bebhinn Treanor, David Depoil, Hisaaki Shinohara, Naomi E Harwood, Masaki Hikida, Facundo D BatistaAbstract:B cell receptor (BCR) recognition of membrane-bound antigen initiates a spreading and contraction response, the extent of which is controlled through the formation of signaling-active BCR-antigen microclusters and ultimately affects the outcome of B cell activation. We followed a genetic approach to define the molecular requirements of BCR-induced spreading and microcluster formation. We identify a key role for phospholipase C-γ2 (PLCγ2), Vav, B cell Linker, and Bruton's tyrosine kinase in the formation of highly coordinated “microsignalosomes,” the efficient assembly of which is absolutely dependent on Lyn and Syk. Using total internal reflection fluorescence microscopy, we examine at high resolution the recruitment of PLCγ2 and Vav to microsignalosomes, establishing a novel synergistic relationship between the two. Thus, we demonstrate the importance of cooperation between components of the microsignalosome in the amplification of signaling and propagation of B cell spreading, which is critical for appropriate B cell activation.
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cbl b positively regulates btk mediated activation of phospholipase c γ2 in b cells
Journal of Experimental Medicine, 2002Co-Authors: Tomoharu Yasuda, Tomohiro Kurosaki, Akito Maeda, Tohru Tezuka, Tetsuya Inazu, Yuji Yamanashi, Tadashi YamamotoAbstract:Genetic studies have revealed that Cbl-b plays a negative role in the antigen receptor–mediated proliferation of lymphocytes. However, we show that Cbl-b–deficient DT40 B cells display reduced phospholipase C (PLC)-γ2 activation and Ca2+ mobilization upon B cell receptor (BCR) stimulation. In addition, the overexpression of Cbl-b in WEHI-231 mouse B cells resulted in the augmentation of BCR-induced Ca2+ mobilization. Cbl-b interacted with PLC-γ2 and helped the association of PLC-γ2 with Bruton's tyrosine kinase (Btk), as well as B cell Linker protein (BLNK). Cbl-b was indispensable for Btk-dependent sustained increase in intracellular Ca2+. Both NH2-terminal tyrosine kinase-binding domain and COOH-terminal half region of Cbl-b were essential for its association with PLC-γ2 and the regulation of Ca2+ mobilization. These results demonstrate that Cbl-b positively regulates BCR-mediated Ca2+ signaling, most likely by influencing the Btk/BLNK/PLC-γ2 complex formation.
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regulation of the phospholipase c gamma2 pathway in b cells
Immunological Reviews, 2000Co-Authors: Tomohiro Kurosaki, A Maeda, M Ishiai, A Hashimoto, K Inabe, M TakataAbstract:In B lymphocytes, a signaling complex that contributes to cell fate decisions is the B-Cell antigen receptor (BCR), with different extents of receptor engagement leading to such outcomes as cell death, survival, or proliferation. Here, based upon the available genetic and biochemical data of the BCR signal components, we discuss several mechanisms by which BCR signals are propagated and modified, with specific emphasis on the phospholipase C (PLC)-gamma2-calcium pathway Gene-targeting experiments in DT40 chicken B cells highlighted the importance of the intracellular protein tyrosine kinases Syk and Btk in PLC-gamma2 activation. Until recently, the molecular mechanism underlying the double requirement for Syk and Btk in PLC-gamma2 activation remained unclear, but new data suggest that an adapter molecule, B-Cell Linker protein (alternatively named SLP-65 or BASH), phosphorylated by Syk, provides docking sites for Btk SH2 domain as well as PLC-gamma2 SH2 domains, thus bringing Btk into close proximity with PLC-gamma2. The activated Btk then phosphorylates PLC-gamma2, leading to its activation. The activated PLC-gamma2 converts phosphatidylinositol 4,5-bisphosphate into the second messenger inositol 1,4,5-trisphosphate (IP3), which in turn binds to IP3 receptors located on the endoplasmic reticulum (ER). Binding of IP3 to the IP3 receptors is essential for triggering a calcium release from the ER and subsequent entry of extracellular calcium. Balancing these activation signals in the PLC-gamma2-calcium pathway are the inhibitory receptors expressed on B cells, FcyRII and paired immunoglobin-like receptor (PIR)-B. Although both FcyRII and PIR-B inhibits the BCR-mediated [Ca2+]i increase, the inhibitory mechanisms of these receptors are distinct. The FcyRII-mediated inhibitory signal is dependent on lipid phosphatase SHIP, whereas the PIR-B requires redundant functions of protein phosphatases SHP-1 and SHP-2. Thus, PIR-B and FcgammaRII inhibit calcium signals by utilizing two distinct signaling molecules, thereby contributing to setting threshold levels for activation signals as well as terminating activation responses.
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cbl suppresses b cell receptor mediated phospholipase c plc γ2 activation by regulating b cell Linker protein plc γ2 binding
Journal of Experimental Medicine, 2000Co-Authors: Tomoharu Yasuda, Akito Maeda, Mari Kurosaki, Tohru Tezuka, Katsunori Hironaka, Tadashi Yamamoto, Tomohiro KurosakiAbstract:Accumulating evidence indicates that the Cbl protein plays a negative role in immune receptor signaling; however, the mode of Cbl action in B cell receptor (BCR) signaling still remains unclear. DT40 B cells deficient in Cbl showed enhanced BCR-mediated phospholipase C (PLC)-γ2 activation, thereby leading to increased apoptosis. A possible explanation for the involvement of Cbl in PLC-γ2 activation was provided by findings that Cbl interacts via its Src homology 2 (SH2) domain with B cell Linker protein (BLNK) after BCR ligation. BLNK is a critical adaptor molecule for PLC-γ2 tyrosine phosphorylation through its binding to the PLC-γ2 SH2 domains. As a consequence of the interaction between Cbl and BLNK, the BCR-induced recruitment of PLC-γ2 to BLNK and the subsequent PLC-γ2 tyrosine phosphorylation were inhibited. Thus, our data suggest that Cbl negatively regulates the PLC-γ2 pathway by inhibiting the association of PLC-γ2 with BLNK.
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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, 1999Co-Authors: Shoji Hashimoto, Akihiro Iwamatsu, Masamichi Ishiai, Katsuya Okawa, Tomoki Yamadori, M Matsushita, Yoshihiro Baba, T Kishimoto, Tomohiro Kurosaki, Satoshi TsukadaAbstract: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.
Andrew C Chan - One of the best experts on this subject based on the ideXlab platform.
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requirement for b cell Linker protein blnk in b cell development
Science, 1999Co-Authors: Rajita Pappu, Alec M Cheng, Qian Gong, Christopher Chiu, Nancy Griffin, Michael A White, Barry P Sleckman, Andrew C ChanAbstract:Linker proteins function as molecular scaffolds to localize enzymes with substrates. In B cells, B cell Linker protein (BLNK) links the B cell receptor (BCR)–activated Syk kinase to the phosphoinositide and mitogen-activated kinase pathways. To examine the in vivo role of BLNK, mice deficient in BLNK were generated. B cell development in BLNK −/− mice was blocked at the transition from B220+CD43+ progenitor B to B220+CD43− precursor B cells. Only a small percentage of immunoglobulin M++ (IgM++), but not mature IgMloIgDhi, B cells were detected in the periphery. Hence, BLNK is an essential component of BCR signaling pathways and is required to promote B cell development.
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an essential role for blnk in human b cell development
Science, 1999Co-Authors: Yoshiyuki Minegishi, Rajita Pappu, Andrew C Chan, Jurg Rohrer, Elaine Coustansmith, Howard M Lederman, Dario Campana, Mary Ellen ConleyAbstract:The signal transduction events that control the progenitor B cell (pro-B cell) to precursor B cell (pre-B cell) transition have not been well delineated. In evaluating patients with absent B cells, a male with a homozygous splice defect in the cytoplasmic adapter protein BLNK (B cell Linker protein) was identified. Although this patient had normal numbers of pro-B cells, he had no pre-B cells or mature B cells, indicating that BLNK plays a critical role in orchestrating the pro-B cell to pre-B cell transition. The immune system and overall growth and development were otherwise normal in this patient, suggesting that BLNK function is highly specific.
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blnk required for coupling syk to plcγ2 and rac1 jnk in b cells
Immunity, 1999Co-Authors: Masamichi Ishiai, Rajita Pappu, Andrew C Chan, Akihiro Iwamatsu, Katsuya Okawa, Mari Kurosaki, Irina Ronko, Masao Shibata, Tomohiro KurosakiAbstract:Abstract Signaling through the B cell receptor (BCR) is essential for B cell function and development. Despite the key role of Syk in BCR signaling, little is known about the mechanism by which Syk transmits downstream effectors. BLNK (B cell Linker protein), a substrate for Syk, is now shown to be essential in activating phospholipase C (PLC)γ2 and JNK. The BCR-induced PLCγ2 activation, but not the JNK activation, was restored by introduction of PLCγ2 membrane-associated form into BLNK-deficient B cells. As JNK activation requires both Rac1 and PLCγ2, our results suggest that BLNK regulates the Rac1-JNK pathway, in addition to modulating PLCγ2 localization.
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BLNK: a Central Linker Protein in B Cell Activation
Immunity, 1998Co-Authors: Christoph W. Turck, Tomohiro Kurosaki, Andrew C ChanAbstract:Abstract Linker or adapter proteins provide mechanisms by which receptors can amplify and regulate downstream effector proteins. We describe here the identification of a novel B cell Linker protein, termed BLNK, that interfaces the B cell receptor–associated Syk tyrosine kinase with PLCγ, the Vav guanine nucleotide exchange factor, and the Grb2 and Nck adapter proteins. Tyrosine phosphorylation of BLNK by Syk provides docking sites for these SH2-containing effector molecules that, in turn, permits the phosphorylation and/or activation of their respective signaling pathways. Hence, BLNK represents a central Linker protein that bridges the B cell receptor–associated kinases with a multitude of signaling pathways and may regulate the biologic outcomes of B cell function and development.
Tsehua Tan - One of the best experts on this subject based on the ideXlab platform.
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actin binding protein 1 links b cell antigen receptors to negative signaling pathways
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Margaret K Seeleyfallen, Lisa J Liu, Melanie R Shapiro, Olusegun O Onabajo, Senthilkumar Palaniyandi, Xiaoping Zhu, Tsehua Tan, Arpita Upadhyaya, Wenxia SongAbstract:Prolonged or uncontrolled B-Cell receptor (BCR) signaling is associated with autoimmunity. We previously demonstrated a role for actin in BCR signal attenuation. This study reveals that actin-binding protein 1 (Abp1/HIP-55/SH3P7) is a negative regulator of BCR signaling and links actin to negative regulatory pathways of the BCR. In both Abp1−/− and bone marrow chimeric mice, in which only B cells lack Abp1 expression, the number of spontaneous germinal center and marginal zone B cells and the level of autoantibody are significantly increased. Serum levels of T-independent antibody responses and total antibody are elevated, whereas T-dependent antibody responses are markedly reduced and fail to undergo affinity maturation. Upon activation, surface BCR clustering is enhanced and B-Cell contraction delayed in Abp1−/− B cells, concurrent with slow but persistent increases in F-actin at BCR signalosomes. Furthermore, BCR signaling is enhanced in Abp1−/− B cells compared with wild-type B cells, including Ca2+ flux and phosphorylation of B-Cell Linker protein, the mitogen-activated protein kinase kinase MEK1/2, and ERK, coinciding with reductions in recruitment of the inhibitory signaling molecules hematopoietic progenitor kinase 1 and SH2-containing inositol 5-phosphatase to BCR signalosomes. Our results indicate that Abp1 negatively regulates BCR signaling by coupling actin remodeling to B-Cell contraction and activation of inhibitory signaling molecules, which contributes to the regulation of peripheral B-Cell development and antibody responses.
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down regulation of b cell receptor signaling by hematopoietic progenitor kinase 1 hpk1 mediated phosphorylation and ubiquitination of activated b cell Linker protein blnk
Journal of Biological Chemistry, 2012Co-Authors: Xiaohong Wang, Tsehua Tan, Hui Kai Kuo, Li Li Chiu, Gregory A Dement, Joungliang Lan, Deryuan Chen, Chia Yu YangAbstract:Hematopoietic progenitor kinase 1 (HPK1) is a Ste20-like serine/threonine kinase that suppresses immune responses and autoimmunity. B cell receptor (BCR) signaling activates HPK1 by inducing BLNK/HPK1 interaction. Whether HPK1 can reciprocally regulate BLNK during BCR signaling is unknown. Here, we show that HPK1-deficient B cells display hyper-proliferation and hyper-activation of IκB kinase and MAPKs (ERK, p38, and JNK) upon the ligation of BCR. HPK1 attenuates BCR-induced cell activation via inducing BLNK threonine 152 phosphorylation, which mediates BLNK/14-3-3 binding. Furthermore, threonine 152-phosphorylated BLNK is ubiquitinated at lysine residues 37, 38, and 42, leading to attenuation of MAPK and IκB kinase activation in B cells during BCR signaling. These results reveal a novel negative feedback regulation of BCR signaling by HPK1-mediated phosphorylation, ubiquitination, and subsequent degradation of the activated BLNK.
Tomoharu Yasuda - One of the best experts on this subject based on the ideXlab platform.
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cbl b positively regulates btk mediated activation of phospholipase c γ2 in b cells
Journal of Experimental Medicine, 2002Co-Authors: Tomoharu Yasuda, Tomohiro Kurosaki, Akito Maeda, Tohru Tezuka, Tetsuya Inazu, Yuji Yamanashi, Tadashi YamamotoAbstract:Genetic studies have revealed that Cbl-b plays a negative role in the antigen receptor–mediated proliferation of lymphocytes. However, we show that Cbl-b–deficient DT40 B cells display reduced phospholipase C (PLC)-γ2 activation and Ca2+ mobilization upon B cell receptor (BCR) stimulation. In addition, the overexpression of Cbl-b in WEHI-231 mouse B cells resulted in the augmentation of BCR-induced Ca2+ mobilization. Cbl-b interacted with PLC-γ2 and helped the association of PLC-γ2 with Bruton's tyrosine kinase (Btk), as well as B cell Linker protein (BLNK). Cbl-b was indispensable for Btk-dependent sustained increase in intracellular Ca2+. Both NH2-terminal tyrosine kinase-binding domain and COOH-terminal half region of Cbl-b were essential for its association with PLC-γ2 and the regulation of Ca2+ mobilization. These results demonstrate that Cbl-b positively regulates BCR-mediated Ca2+ signaling, most likely by influencing the Btk/BLNK/PLC-γ2 complex formation.
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cbl suppresses b cell receptor mediated phospholipase c plc γ2 activation by regulating b cell Linker protein plc γ2 binding
Journal of Experimental Medicine, 2000Co-Authors: Tomoharu Yasuda, Akito Maeda, Mari Kurosaki, Tohru Tezuka, Katsunori Hironaka, Tadashi Yamamoto, Tomohiro KurosakiAbstract:Accumulating evidence indicates that the Cbl protein plays a negative role in immune receptor signaling; however, the mode of Cbl action in B cell receptor (BCR) signaling still remains unclear. DT40 B cells deficient in Cbl showed enhanced BCR-mediated phospholipase C (PLC)-γ2 activation, thereby leading to increased apoptosis. A possible explanation for the involvement of Cbl in PLC-γ2 activation was provided by findings that Cbl interacts via its Src homology 2 (SH2) domain with B cell Linker protein (BLNK) after BCR ligation. BLNK is a critical adaptor molecule for PLC-γ2 tyrosine phosphorylation through its binding to the PLC-γ2 SH2 domains. As a consequence of the interaction between Cbl and BLNK, the BCR-induced recruitment of PLC-γ2 to BLNK and the subsequent PLC-γ2 tyrosine phosphorylation were inhibited. Thus, our data suggest that Cbl negatively regulates the PLC-γ2 pathway by inhibiting the association of PLC-γ2 with BLNK.
Mari Kurosaki - One of the best experts on this subject based on the ideXlab platform.
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cbl suppresses b cell receptor mediated phospholipase c plc γ2 activation by regulating b cell Linker protein plc γ2 binding
Journal of Experimental Medicine, 2000Co-Authors: Tomoharu Yasuda, Akito Maeda, Mari Kurosaki, Tohru Tezuka, Katsunori Hironaka, Tadashi Yamamoto, Tomohiro KurosakiAbstract:Accumulating evidence indicates that the Cbl protein plays a negative role in immune receptor signaling; however, the mode of Cbl action in B cell receptor (BCR) signaling still remains unclear. DT40 B cells deficient in Cbl showed enhanced BCR-mediated phospholipase C (PLC)-γ2 activation, thereby leading to increased apoptosis. A possible explanation for the involvement of Cbl in PLC-γ2 activation was provided by findings that Cbl interacts via its Src homology 2 (SH2) domain with B cell Linker protein (BLNK) after BCR ligation. BLNK is a critical adaptor molecule for PLC-γ2 tyrosine phosphorylation through its binding to the PLC-γ2 SH2 domains. As a consequence of the interaction between Cbl and BLNK, the BCR-induced recruitment of PLC-γ2 to BLNK and the subsequent PLC-γ2 tyrosine phosphorylation were inhibited. Thus, our data suggest that Cbl negatively regulates the PLC-γ2 pathway by inhibiting the association of PLC-γ2 with BLNK.
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blnk required for coupling syk to plcγ2 and rac1 jnk in b cells
Immunity, 1999Co-Authors: Masamichi Ishiai, Rajita Pappu, Andrew C Chan, Akihiro Iwamatsu, Katsuya Okawa, Mari Kurosaki, Irina Ronko, Masao Shibata, Tomohiro KurosakiAbstract:Abstract Signaling through the B cell receptor (BCR) is essential for B cell function and development. Despite the key role of Syk in BCR signaling, little is known about the mechanism by which Syk transmits downstream effectors. BLNK (B cell Linker protein), a substrate for Syk, is now shown to be essential in activating phospholipase C (PLC)γ2 and JNK. The BCR-induced PLCγ2 activation, but not the JNK activation, was restored by introduction of PLCγ2 membrane-associated form into BLNK-deficient B cells. As JNK activation requires both Rac1 and PLCγ2, our results suggest that BLNK regulates the Rac1-JNK pathway, in addition to modulating PLCγ2 localization.
