Stimulus-Dependent Inhibitor of Apoptosis Protein Expression Prolongs the Duration of B Cell Signalling.
Different dynamic behaviours of signalling activity can induce distinct biological responses in a variety of cells. However, the molecular mechanisms that determine the dynamics of kinase activities in immune cells are not well understood. In this study, we showed that the duration of both IκB kinase (IKK) and extracellular signal-regulated kinase (ERK) activities in B cell receptor (BCR)- and CD40-signalling pathways in B cells were regulated by transcriptional feedback loops. We conducted a time-course transcriptome analysis after BCR or CD40 stimulation and identified the following four candidate genes as feedback regulators for IKK and ERK: inhibitor of apoptosis protein (IAP), TNF alpha-induced protein 3, dual-specificity phosphatase 5, and sprouty homolog 2. Quantitative experiments and mathematical modelling suggested that IAP inhibition shortened the duration of IKK and ERK activity following both BCR and CD40 pathway stimulation, indicating a positive role for IAP in B cell signalling. Furthermore, transient kinase activities induced by IAP blockage reduced the levels of delayed expression genes. Together, our findings suggest that IKK and ERK activity durations can be fine-tuned by the coordinated regulation of positive and negative transcriptional feedback and that these network properties determine the biological output of B cells.
Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan.
Hisaaki
H
Shinohara
Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan.
Kentaro
K
Inoue
Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan.
Noriko
N
Yumoto
Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan.
Takeshi
T
Nagashima
Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan.
Mariko
M
Okada-Hatakeyama
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D023201:CD40 Ligand / Q000494:pharmacology*; D002460:Cell Line; D054637:Dual-Specificity Phosphatases / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics; D025461:Feedback, Physiological; D051550:I-kappa B Kinase / Q000235:genetics; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D017346:Protein Serine-Threonine Kinases; D051562:Proto-Oncogene Proteins c-bcr / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics
D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011947:Receptors, Antigen, B-Cell; D023201:CD40 Ligand; D017346:Protein Serine-Threonine Kinases; D051562:Proto-Oncogene Proteins c-bcr; C118389:Spry2 protein, mouse; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D054637:Dual-Specificity Phosphatases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C513261:Tnfaip3 protein, mouse