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The interaction between CD300f and its ligand ceramide suppresses IgE-mediated mast cell activation and anaphylactic responses through phosphorylation of immunoreceptor tyrosine-based inhibitory and switch motifs.[2] CD300f also regulates gut inflammation by different mechanisms.[[3]] Nevertheless, it remains unknown whether CD300f regulates the development of food allergy. Serum levels of total IgE (C), OVA-specific IgE (D) and MCPT-1 (E), and the numbers of jejunum mast cells (F) in WT and CD300f-/- (KO) mice after the last challenge. According to numerous studies, Tregs inhibit both Th2 skewing, involving food antigen-specific IgE production and IL-9-mediated mast cell hyperplasia, and IgE/antigen-mediated mast cell activation, which are pivotal in the development of food allergy, whereas Th2- and mast cell-derived cytokines (eg, IL-4) downregulate Tregs.[[1], [6], [9]] Accordingly, CD300f in intestinal mast cells (possibly in concert with CD103 SP + sp CD11b SP + sp cells) inhibits the development of OVA-induced food allergy by suppressing mast cell activation with the skewing of Th2/Treg balance toward Th2. [Extracted from the article]

Transforming growth factor-β (TGF-β)-stimulated clone-22 (TSC-22), also called TSC22D1-2, is a putative tumor suppressor. We previously identified TSC-22 downstream of an active mutant of fms-like tyrosine kinase-3 (Flt3). Here, we show that TSC-22 works as a tumor suppressor through inhibiting Ras/Raf signaling. Notably, TSC-22 was upregulated by Ras/Raf activation, whereas its upregulation was inhibited by concurrent STAT5 activation. Although TSC-22 was normally retained in the cytoplasm by its nuclear export signal (NES), Ras/Raf activation caused nuclear translocation of TSC-22, but not TSC22D1-1. Unlike glucocorticoid-induced leucine zipper (GILZ/TSC22D3-2) previously characterized as a negative regulator of Ras/Raf signaling, TSC-22 failed to interact physically with Ras/Raf. Importantly, transduction with TSC-22, but not TSC22D1-1, suppressed the growth, transformation and tumorigenesis of NIH3T3 cells expressing oncogenic H-Ras: this suppression was enhanced by transduction with a TSC-22 mutant lacking NES that had accumulated in the nucleus. Collectively, upregulation and nuclear translocation of TSC-22 played an important role in the feedback suppression of Ras/Raf signaling. Consistently, TSC22D1-deficient mice were susceptible to tumorigenesis in a mouse model of chemically-induced liver tumors bearing active mutations of Ras/Raf. Thus, TSC-22 negatively regulated Ras/Raf signaling through a mechanism different from GILZ, implicating TSC-22 as a novel suppressor of oncogenic Ras/Raf-induced tumors. ( Cancer Sci 2012; 103: 26-33) [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is a clonal disorder of hematopietic stem cells characterized by ineffective hematopoiesis, peripheral blood cytopenia, morphologic dysplasia, and susceptibility to acute myeloid leukemia. Several mechanisms have been suggested as causes of MDS: unbalanced chromosomal abnormalities reflecting a gain or loss of chromosomal material, point mutations of transcription factors, and inactivation of p53. However, appropriate animal models that mimic MDS have long been lacking. We recently reported a novel murine model of MDS that recapitulates trilineage dysplasia and transformation to AML. In this review, we summarize the animal models of MDS and discuss the molecular bases of MDS as well as those of leukemia and myeloproliferative disorders (MPD). J. Cell. Physiol. 219: 529–534, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Mutations in Bruton's tyrosine kinase (Btk) result in X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. While targeted disruption of the protein kinase C-β (PKCβ) gene in mice results in an immunodeficiency similar to xid, the overall tyrosine phosphorylation of Btk is significantly enhanced in PKCβ-deficient B cells. We provide direct evidence that PKCβ acts as a feedback loop inhibitor of Btk activation. Inhibition of PKCβ results in a dramatic increase in B-cell receptor (BCR)-mediated Ca2+ signaling. We identified a highly conserved PKCβ serine phosphorylation site in a short linker within the Tec homology domain of Btk. Mutation of this phosphorylation site led to enhanced tyrosine phosphorylation and membrane association of Btk, and augmented BCR and Fc∊RI-mediated signaling in B and mast cells, respectively. These findings provide a novel mechanism whereby reversible translocation of Btk/Tec kinases regulates the threshold for immunoreceptor signaling and thereby modulates lymphocyte activation. [ABSTRACT FROM AUTHOR]