TAK1 maintains the survival of immunoglobulin λ‐chain‐positive B cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135064/1/gtc12442-sup-0001-FigS1-S6.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135064/2/gtc12442.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135064/3/gtc12442_am.pd

IκB kinase β–induced phosphorylation of CARMA1 contributes to CARMA1–Bcl10–MALT1 complex formation in B cells

Protein kinase C (PKC) β has been reported (Shinohara, H., T. Yasuda, Y. Aiba, H. Sanjo, M. Hamadate, H. Watarai, H. Sakurai, and T. Kurosaki. 2005. J. Exp. Med. 202:1423–1431; Sommer, K., B. Guo, J.L. Pomerantz, A.D. Bandaranayake, M.E. Moreno-Garcia, Y.L. Ovechkina, and D.J. Rawlings. 2005. Immunity. 23:561–574) to play a crucial role in B cell receptor (BCR)–mediated IκB kinase (IKK) activation through phosphorylation of caspase recruitment domain 11, Bimp3 (CARMA1). However, it remains unclear whether this PKCβ-mediated phosphorylation accounts fully for the activation status of CARMA1, because involvement of other kinases, such as phosphoinositide 3-kinase–dependent kinase 1, has also been suggested. We show that PKCβ mediates phosphorylation of CARMA1 on Ser668, which in turn is essential for BCR-mediated CARMA1–Bcl10–mucosal-associated lymphoid tissue 1 (MALT1) association and subsequent IKK activation. Our analyses also demonstrate that the downstream kinase IKKβ contributes to facilitating formation of the complex CARMA1–Bcl10–MALT1 by mediating phosphorylation of CARMA1. Hence, our data suggest that PKCβ is crucial for initial activation of IKK. The activated IKKβ does not merely function as an effector enzyme but also modifies the upstream signaling complex through a feedback mechanism, thereby optimizing the strength and duration of the nuclear factor κB signal

Oscillation dynamics underlie functional switching of NF-κB for B-cell activation.

Transcription factor nuclear factor kappa B (NF-κB) shows cooperative switch-like activation followed by prolonged oscillatory nuclear translocation in response to extracellular stimuli. These dynamics are important for activation of the NF-κB transcriptional machinery, however, NF-κB activity regulated by coordinated actions of these dynamics has not been elucidated at the system level. Using a variety of B cells with artificially rewired NF-κB signaling networks, we show that oscillations and switch-like activation of NF-κB can be dissected and that, under some conditions, these two behaviors are separated upon antigen receptor activation. Comprehensive quantitative experiments and mathematical analysis showed that the functional role of switch activation in the NF-κB system is to overcome transient IKK (IκB kinase) activity to amplify nuclear translocation of NF-κB, thereby inducing the prolonged NF-κB oscillatory behavior necessary for target gene expression and B-cell activation

Comparative survey of go/no-go results to identify the inhibitory control ability change of Japanese children

This research, conducted in 1998 and 2008, uses go/no-go data to investigate the fundamentals of cognitive functioning in the inhibitory control ability of Japanese children. 844 subjects from kindergarten to junior high school participated in go/no-go task experiments. Performance of go/no-go tasks, which are frequently used to investigate response inhibition, measures a variety of cognitive components besides response inhibition. With normal brain development, the ability to inhibit responses improves substantially in adolescence. An increase over time in the error rate during the go/no-go tasks of subjects of the same age indicates that these processes are not functioning properly. Comparisons between the 1998 and 2008 data revealed several differences in error rates. In 2008, there were increases in the number of errors in groups from each age range. The comparison also revealed that overall error rates peaked at later ages in the 2008 subjects. Taken together, these results show changing conditions in the inhibitory function of the prefrontal cortex. However, the reason for these changing conditions remains unclear. While a lifestyle questionnaire revealed several differences in factors such as bedtimes and hours spent watching TV, analysis did not reveal a significant correlation.ArticleBioPsychoSocial Medicine.8(1):14(2014)journal articl

Comparison of cortical activation during Mahjong game play in a video game setting and a real-life setting

The purpose of this study was to compare the hemodynamic changes that occur during Mahjong game play in virtual and real-life settings. Fourteen healthy right-handed men (average age ± standard deviation; 36.7 ± 14.9 years) played: 1) a Mahjong solitaire game on a video console against virtual rivals; 2) a Mahjong game against human opponents without conversation; and 3) a Mahjong game against human opponents with conversation. We measured oxygenated hemoglobin concentration at 44 locations over both hemispheres during Mahjong game play in each setting using near-infrared spectroscopy. The increase in oxygenated hemoglobin concentration at several locations, including Broca’s area, the somatosensory cortex, the somatosensory association cortex, the supramarginal gyrus part of Wernicke’s area, the primary and auditory association cortex, the angular gyrus part of Wernicke’s area, and the associative visual cortex was greater during game play in the real-life settings than during game play in the video game setting. There were no significant differences during game play in real-life settings without and with conversation. Each cortical area correlated with broad or specific areas. The common correlation areas were found at Angular gyrus part of Wernicke’s area of left hemisphere during real-life settings without and with conversation, but not during game play in a video game setting. These results suggest that the brain responds differently to game play in real world and virtual world settings, and indicate that comparison of games played in the virtual world and the real world may be an effective model to enhance understanding of the effects of video game on the brain.ArticleBiochemistry & Analytical Biochemistry.4(2):164(2015)journal articl

Phospholipase C-γ2 and Vav cooperate within signaling microclusters to propagate B cell spreading in response to membrane-bound antigen

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

Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling

Endotoxin, a bacterial lipopolysaccharide (LPS), causes fatal septic shock via Toll-like receptor (TLR)4 on effector cells of innate immunity like macrophages, where it activates nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinases to induce proinflammatory cytokines such as tumor necrosis factor (TNF)-α. Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras–Erk signaling downstream of protein tyrosine kinases (PTKs). Here, we demonstrate that LPS rapidly induced the tyrosine phosphorylation and adaptor function of these proteins. The stimulation with LPS of macrophages from mice lacking Dok-1 or Dok-2 induced elevated Erk activation, but not the other MAP kinases or NF-κB, resulting in hyperproduction of TNF-α and nitric oxide. Furthermore, the mutant mice showed hyperproduction of TNF-α and hypersensitivity to LPS. However, macrophages from these mutant mice reacted normally to other pathogenic molecules, CpG oligodeoxynucleotides, poly(I:C) ribonucleotides, or Pam3CSK4 lipopeptide, which activated cognate TLRs but induced no tyrosine phosphorylation of Dok-1 or Dok-2. Forced expression of either adaptor, but not a mutant having a Tyr/Phe substitution, in macrophages inhibited LPS-induced Erk activation and TNF-α production. Thus, Dok-1 and Dok-2 are essential negative regulators downstream of TLR4, implying a novel PTK-dependent pathway in innate immunity

Role of Dok-1 and Dok-2 in Myeloid Homeostasis and Suppression of Leukemia

Dok-1 and Dok-2 are closely related rasGAP-associated docking proteins expressed preferentially in hematopoietic cells. Although they are phosphorylated upon activation of many protein tyrosine kinases (PTKs), including those coupled with cytokine receptors and oncogenic PTKs like Bcr-Abl, their physiological roles are largely unidentified. Here, we generated mice lacking Dok-1 and/or Dok-2, which included the double-deficient mice succumbed to myeloproliferative disease resembling human chronic myelogenous leukemia (CML) and chronic myelomonocytic leukemia. The double-deficient mice displayed medullary and extramedullary hyperplasia of granulocyte/macrophage progenitors with leukemic potential, and their myeloid cells showed hyperproliferation and hypo-apoptosis upon treatment and deprivation of cytokines, respectively. Consistently, the mutant myeloid cells showed enhanced Erk and Akt activation upon cytokine stimulation. Moreover, loss of Dok-1 and/or Dok-2 induced blastic transformation of chronic phase CML-like disease in mice carrying the bcr-abl gene, a cause of CML. These findings demonstrate that Dok-1 and Dok-2 are key negative regulators of cytokine responses and are essential for myeloid homeostasis and suppression of leukemia