Mnk1 and Mnk2 are protein kinases that are directly phosphorylated and activated by extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein (MAP) kinases and implicated in the regulation of protein synthesis through their phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) at Ser209. To investigate their physiological functions, we generated mice lacking the Mnk1 or Mnk2 gene or both; the resulting KO mice were viable, fertile, and developed normally. In embryonic fibroblasts prepared from Mnk1-Mnk2 DKO mice, eIF4E was not detectably phosphorylated at Ser209, even when the ERK and/or p38 MAP kinases were activated. Analysis of embryonic fibroblasts from single KO mice revealed that Mnk1 is responsible for the inducible phosphorylation of eIF4E in response to MAP kinase activation, whereas Mnk2 mainly contributes to eIF4E's basal, constitutive phosphorylation. Lipopolysaccharide (LPS)-or insulininduced upregulation of eIF4E phosphorylation in the spleen, liver, or skeletal muscle was abolished in Mnk1 ؊/؊ mice, whereas the basal eIF4E phosphorylation levels were decreased in Mnk2 ؊/؊ mice. In Mnk1-Mnk2 DKO mice, no phosphorylated eIF4E was detected in any tissue studied, even after LPS or insulin injection. However, neither general protein synthesis nor cap-dependent translation, as assayed by a bicistronic reporter assay system, was affected in Mnk-deficient embryonic fibroblasts, despite the absence of phosphorylated eIF4E. Thus, Mnk1 and Mnk2 are exclusive eIF4E kinases both in cultured fibroblasts and adult tissues, and they regulate inducible and constitutive eIF4E phosphorylation, respectively. These results strongly suggest that eIF4E phosphorylation at Ser209 is not essential for cell growth during development.Mitogen-activated protein kinases (MAPKs) are activated by various extracellular signals, such as growth factors, stresses, and cytokines, and play crucial roles in the determination of cell fate through proliferation, differentiation, survival, and apoptosis (1,5,24,38) . Three classes of MAPK families, the ERK, Jun N-terminal kinase/stress-activated protein kinase, and p38 MAPK, are differentially activated depending on the signaling context and in turn phosphorylate target proteins, which include transcription factors and protein kinases. These proteins can be common targets for subsets of MAPK proteins or specific targets for individual MAPKs. The direct downstream protein kinases, comprehensively called the MAPKactivated protein kinase (MAPKAPK) family, can be categorized into four subclasses, the Rsk, MK, Mnk, and Msk families. The Rsks (Rsk1, Rsk2, and Rsk3) are activated specifically by ERKs, whereas the MKs (MK2/MAPKAPK2, MK3/ MAPKAPK3/3pK, and MK5/PRAK) are activated mainly by p38 MAPK in vivo. In contrast, the Mnks (Mnk1 and Mnk2) and Msks (Msk1 and Msk2) are targeted in vivo by both the ERK and p38 MAPK pathways, resulting in the activation of Mnks and Msks by a broad spectrum of extracellular stimuli.Mnk1 (MAPK signal-integrating kinase 1/MAPK-int...

Despite the importance of memory B cells in protection from reinfection, how such memory cells are selected and generated during germinal-center (GC) reactions remains unclear. We found here that light-zone (LZ) GC B cells with B cell antigen receptors (BCRs) of lower affinity were prone to enter the memory B cell pool. Mechanistically, cells in this memory-prone fraction had higher expression of the transcriptional repressor Bach2 than that of their counterparts with BCRs of higher affinity. Haploinsufficiency of Bach2 resulted in reduced generation of memory B cells, independently of suppression of the gene encoding the transcription factor Blimp-1. Bach2 expression in GC cells was inversely correlated with the strength of help provided by T cells. Thus, we propose an instructive model in which weak help from T cells maintains relatively high expression of Bach2, which predisposes GC cells to enter the memory pool.

Mature erythrocytes in mammals have no nuclei, although they differentiate from nucleated precursor cells. The mechanism by which enucleation occurs is not well understood. Here we show that deoxyribonuclease II (DNase II) is indispensable for definitive erythropoiesis in mouse fetal liver. No live DNase II-null mice were born, owing to severe anemia. When mutant fetal liver cells were transferred into lethally irradiated wild-type mice, mature red blood cells were generated from the mutant cells, suggesting that DNase II functions in a non-cell-autonomous manner. Histochemical analyses indicated that the critical cellular sources of DNase II are macrophages present at the site of definitive erythropoiesis in the fetal liver. Thus, DNase II in macrophages appears to be responsible for destroying the nuclear DNA expelled from erythroid precursor cells.