Phong et al. show that depending on the expression of p-Lyn, mast cell activation by antigen can result in dichotomous effects on mast cell function and signaling that can be accentuated by Tim-3 ligation.

Signaling to the mechanistic target of rapamycin (mTOR) regulates diverse cellular processes, including protein translation, cellular proliferation, metabolism, and autophagy. These effects are mediated in part by the mTOR targets S6 kinase (S6K) and eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). Most models place Akt upstream of the best-studied mTOR complex, mTORC1; however, studies have called into question whether Akt is necessary for this pathway, at least in T cells. We found that the adaptor protein Carma1 [caspase recruitment domain (CARD)-containing membrane-associated protein 1 (Carma1)] and at least one of its associated proteins, the paracaspase MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), were required for optimal activation of mTOR in T cells in response to stimulation of the T cell receptor (TCR) and the coreceptor CD28. However, another common binding partner of Carma1 and MALT1, Bcl10, was not required for TCR-dependent activation of the mTOR pathway. Consistent with these findings, MALT1 activity was required for the proliferation of CD4 + T cells, but not early TCR-dependent activation events. Also consistent with an effect on mTOR, MALT1 activity was required for the increased metabolic flux in activated CD4 + T cells. Together, our data suggest that Carma1 and MALT1 play previously unappreciated roles in the activation of mTOR signaling in T cells after engagement of the TCR.

Background: The precise role of the Akt kinase in NF-B induction by the TCR and CD28 is still unclear. Results: We have found that Akt makes a quantitative contribution to NF-B induction in T cells, selectively impacting a subset of downstream genes. Conclusion: Although Akt is not a canonical member of the NF-B pathway, it can modulate NF-B signaling and transcription. Significance: These findings may open the way to more selective modulation of NF-B-dependent pathways.

There is growing appreciation that cellular metabolic and bioenergetic pathways do not play merely passive roles in activated leukocytes. Rather, metabolism plays important roles in controlling cellular activation, differentiation, survival and effector function. Much of this work has been performed in T cells; however, there is still very little information regarding mast cell metabolic reprogramming and its effect on cellular function. Mast cells perform important barrier functions and help control type 2 immune responses. Here we show here that murine bone marrow derived mast cells rapidly alter their metabolism in response to stimulation through the Fc receptor for IgE (FcεRI). We also demonstrate that specific metabolic pathways appear to be differentially required for control of mast cell function. Manipulation of metabolic pathways may represent a novel point for manipulation of mast cell activation.

EAF2, an androgen-regulated protein, interacts with members of the ELL (eleven-nineteen lysine-rich leukemia) transcription factor family and also acts as a tumor suppressor. Although these proteins control transcriptional elongation and perhaps modulate the effects of other transcription factors, the mechanisms of their actions remain largely unknown. To gain new insights into the biology of the EAF2 and ELL family proteins, we used Caenorhabditis elegans as a model to explore the in vivo roles of their worm orthologs. Through the use of transgenic worms, RNAi, and an eaf-1 mutant, we found that both genes are expressed in multiple cell types throughout the worm life cycle and that they play important roles in fertility, survival, and body size regulation. ELL-1 and EAF-1 likely contribute to these activities in part through modulating cuticle synthesis, given that we observed a disrupted cuticle structure in ell-1 RNAi-treated or eaf-1 mutant worms. Consistent with disruption of cuticle structure, loss of either ELL-1 or EAF-1 suppressed the rol phenotype of specific collagen mutants, possibly through the control of dpy-3, dpy-13, and sqt-3 collagen gene expression. Furthermore, we also noted the regulation of collagen expression by ELL overexpression in PC3 human prostate cancer cells. Together, these results reveal important roles for the eaf-1 and ell-1 genes in the regulation of extracellular matrix components.Androgens play a key role in prostate development, prostate cancer, and benign prostatic hyperplasia. Thus, identification and characterization of androgen-responsive genes could significantly contribute to the prevention and treatment of prostate cancer and benign prostatic hyperplasia. One such androgen-responsive gene is EAF2 (ELL-associated factor 2), which may serve as a tumor suppressor (1). The EAF2 locus exhibits frequent allelic loss in ϳ80% of advanced clinical prostate cancer specimens, and evidence for homozygous deletion also exists (1). EAF2 deficiency in mice leads to carcinogenesis in multiple tissues (2) as well as aspermatogenesis and reduced survival (3). In addition to EAF2, mammals also express EAF1, a protein that shares 58% identity and 74% similarity with EAF2. Both EAF proteins interact with the ELL family of transcription elongation factors, including ELL, ELL2, and ELL3 (4 -9). ELL has been identified in an array of species, including yeast (10), Drosophila (11), zebrafish (12), mouse (13), and human (14). This widely expressed gene is essential for embryonic development because deletion of ELL in mouse or Drosophila causes embryonic lethality (15,16). ELL also plays an important role in leukemia (8,17). Chromosomal translocation can lead to fusion of ELL with the MLL (multiple lineage leukemia) gene, and the MLL-ELL fusion protein can cause acute myeloid leukemia (8,18).The mechanisms of EAF/ELL action appear to be complex and involve multiple signaling pathways. ELL family proteins interact with RNA polymerase II and act as a transcription elongation factor (4, 19). Eisse...