DRAK2, a lymphoid-enriched DAP kinase, regulates the TCR activation threshold during thymocyte selection

Department of Molecular Biology and Biochemistry, Center for Immunology, University of California-Irvine, Irvine, CA 92697-3900, USA.
International Immunology (Impact Factor: 2.54). 12/2005; 17(11):1379-90. DOI: 10.1093/intimm/dxh315
Source: PubMed


DAP kinases are a family of serine/threonine kinases known to regulate intrinsic apoptotic processes. DAP-related apoptotic
kinase-2 (DRAK2) is highly expressed in lymphoid organs, with differential expression during thymocyte development. Low levels
of transcript were observed in CD4/CD8 double-positive (DP) and double-negative populations, whereas single-positive thymocytes
possessed elevated levels. Ex vivo stimulation of DP thymocytes with phorbol myristate acetate or antibodies that activate the TCR complex led to the accumulation
of DRAK2 in a protein kinase C- and MAP Kinase-dependent fashion. Although DAP kinase family members are thought to potentiate
apoptosis, ectopic expression of DRAK2 using retroviral transduction of primary T cells and NIH3T3 fibroblasts failed to decrease
rates of survival, suggesting that DRAK2 expression is not sufficient to promote apoptosis. Rather, our results demonstrate
that DRAK2 is a primary response gene activated by TCR stimulation in DP thymocytes. Further, we observed that DRAK2 controlled
the threshold for calcium signaling in the thymus since positively selected Drak2-deficient thymocytes displayed a reduced requirement for TCR cross-linking. These findings are consistent with a role for
DRAK2 in thymocyte selection and lymphoid maturation, and demonstrate that DRAK2 transduces non-apoptotic signals during thymocyte

Download full-text


Available from: Cornelis Murre, Apr 01, 2014
  • Source
    • "Although broadly expressed at low levels (127), DRAK2 expression is enriched in cells of hematopoietic origin (128). Loss of expression by virtue of a germline deletion of the Drak2 gene leads to hyperactive Ca2+ mobilization in T cells, especially under suboptimal TCR stimulus conditions (128, 129), supporting the hypothesis that DRAK2 acts as a negative regulator of TCR signaling (130). "
    [Show abstract] [Hide abstract]
    ABSTRACT: As a vital second messenger in the activation of lymphocytes, the divalent cation Ca(2+) plays numerous roles in adaptive immune responses. Importantly, Ca(2+) signaling is essential for T cell activation, tolerance of self-antigens, and homeostasis. Supporting the essential role of Ca(2+) signaling in T cell biology, the Ca(2+) regulated protein phosphatase calcineurin is a key target of pharmacologic inhibition for preventing allograft rejection and for autoimmune therapy. Recent studies have highlighted the unique role of Stim1 and Orai1/2 proteins in the regulation of store-operated/calcium release activated calcium (CRAC) channels in the context of T cells. While Ca(2+) is known to modulate T cell activation via effects on calcineurin and its target, nuclear factor of activated T cells (NFAT), this second messenger also regulates other pathways, including protein kinase C, calmodulin kinases, and cytoskeletal proteins. Ca(2+) also modulates the unique metabolic changes that occur during in distinct T cell stages and subsets. Herein, we discuss the means by which Ca(2+) mobilization modulates cellular metabolism following T cell receptor ligation. Further, we highlight the crosstalk between mitochondrial metabolism, reactive oxygen species (ROS) generation, and CRAC channel activity. As a target of mitochondrial ROS and Ca(2+) regulation, we describe the involvement of the serine/threonine kinase DRAK2 in the context of these processes. Given the important roles for Ca(2+) dependent signaling and cellular metabolism in adaptive immune responses, the crosstalk between these pathways is likely to be important for the regulation of T cell activation, tolerance, and homeostasis.
    Full-text · Article · Oct 2013 · Frontiers in Immunology
  • Source
    • "Finally, the positively selected B cells are provided a survival signals by T h cells to differentiate into plasma and memory B cells, which have the capacity to produce high affinity class-switched antibodies [26] [27]. Despite accumulating evidence that DRAK2 is involved in T-cell signaling and autoimmunity [5] [8] [10], little is known about its role in the development of a specific antibody response. Here, we used DRAK2-deficient B cells and DRAK2-deficient mice to address the role of DRAK2 in the maturation of the antibody response. "
    [Show abstract] [Hide abstract]
    ABSTRACT: DAP-related apoptotic kinase-2 (DRAK2), a death-associated protein kinase family member, is highly expressed in B and T lymphocytes in the human and the mouse. To determine whether DRAK2 plays a role in B-cell activation and differentiation, we analyzed germinal centers (GCs) and the specific antibody response to NP in drak2-/- mice immunized with the thymus-dependent (TD) conjugated hapten NP16-CGG. In drak2-/- mice, spleen GCs were normal in size and morphology, but their number was reduced by as much as 5-fold, as compared to their wild-type littermates. This was not due to a defect in B-cell proliferation, as the BrdU uptake was comparable in DRAK2-deficient and wild-type B cells. Rather, the proportion of apoptotic GC B and T cells in drak2-/- mice was significantly higher than that in wild-type control mice, as shown by 7-AAD and terminal deoxynucleotide transferase dUTP nick end labeling (TUNEL) staining. In drak2-/- mice, the generation high affinity IgG antibodies was impaired in spite of the seemingly normal somatic hypermutation and class switch DNA recombination machineries in drak2-/- B cells. In NP16-CGG-immunized drak2-/- mice, T-cell-intrinsic Bcl-xL transgene expression increased the number of GCs and rescued the high affinity IgG response to NP. These findings suggest a novel role for DRAK2 in regulating the GC reaction and the response to TD antigens, perhaps through increased survival of T cells and enhanced B-cell positive selection. They also suggest that DRAK2-deficiency is not involved in regulating intrinsic B-cell apoptosis.
    Full-text · Article · Sep 2008 · Autoimmunity
  • Source
    • "With respect to DRAK 1 and 2, less data exist. DRAK 1 from rabbits has been shown to play a role in osteoclastspecific cell death [16] and DRAK 2 appears to be involved in T-cell-specific processes, perhaps thymocyte selection and maturation [17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dlk/ZIP kinase is a member of the DAP kinase family which has been implicated in apoptosis. However, Dlk/ZIP kinase does not induce apoptosis per se. Rather, downregulation of Dlk/ZIP kinase by siRNA results in apoptosis and multinucleated cells suggesting that Dlk/ZIP kinase fulfills a vital function in processes other than apoptosis. Indeed, Dlk/ZIP kinase interacts with several transcription and splicing factors pointing to a role in transcription, presumably via chromatin modification. Moreover, it appears to participate in regulation of cell polarity and contractile processes in non-muscle or smooth muscle cells. Finally, Dlk/ZIP kinase seems to play a role in mitosis, particularly cytokinesis. Thus, rather than being a proapoptotic kinase, Dlk/ZIP kinase participates in diverse and vital processes.
    Preview · Article · Jun 2007 · Signal Transduction
Show more