McGargill MA, Wen BG, Walsh CM, Hedrick SMA deficiency in Drak2 results in a T cell hypersensitivity and an unexpected resistance to autoimmunity. Immunity 21: 781-791

Division of Biological Sciences, Department of Cellular and Molecular Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093 USA.
Immunity (Impact Factor: 21.56). 01/2005; 21(6):781-91. DOI: 10.1016/j.immuni.2004.10.008
Source: PubMed


DRAK2 is a member of the death-associated protein (DAP)-like family of serine/threonine kinases. Members of this family induce apoptosis in various cell types. DRAK2, in particular, is specifically expressed in T cells and B cells, and it is differentially regulated during T cell development. To determine whether DRAK2 regulates lymphocyte apoptosis, we produced Drak2(-/-) mice. Contrary to our expectations, Drak2(-/-) T cells did not demonstrate any defects in apoptosis or negative selection; however, T cells from Drak2(-/-) mice exhibited enhanced sensitivity to T cell receptor-mediated stimulation with a reduced requirement for costimulation. These results provide evidence that DRAK2 raises the threshold for T cell activation by negatively regulating signals through the TCR. In contrast to other models of T cell hypersensitivity, Drak2(-/-) mice were remarkably resistant to experimental autoimmune encephalomyelitis (EAE). These results expose a new pathway regulating T cell activation and highlight the intricacies of induced autoimmune disease.

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Available from: Maureen A Mcgargill
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    • "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). The notion that DRAK2 serves as a rheostat in calcium signaling following TCR signaling is supported by the finding that it is itself activated by calcium mobilization, and that its ectopic expression in double positive thymocytes raises the threshold for both negative and positive selection (131, 132). "
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    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.
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    • "RAFTLIN (raft-linking protein) was also shown to influence T-cell mediated immune responses and Th17 differentiation [31]. STK17B is a serine kinase also known as DRAK (DAP kinase-related apoptosis-inducing kinase) 2 which is known to mediate apoptosis induced by IL-2 and regulate T cell receptor sensitivity in developing thymocytes [32]–[33]. Phosphodiesterase (PDE) 4 B is a type 4 PDE (up ∼2-fold) that regulates TCR signaling by tempering the negative effect of cAMP [34] and in CD4+ human T cells decreased PDE4B expression leads to reduced IL-2 production upon anti-CD3/CD28 co-stimulation [35]. The chip-on-ChIP identified STAT5 binding site within the PDE4B is shown in Figure 4B, visualized by the IGV. "
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    ABSTRACT: IL-2 is the primary growth factor for promoting survival and proliferation of activated T cells that occurs following engagement of the Janus Kinase (JAK)1-3/and Signal Transducer and Activator of Transcription (STAT) 5 signaling pathway. STAT5 has two isoforms: STAT5A and STAT5B (commonly referred to as STAT5) which, in T cells, play redundant roles transcribing cell cycle and survival genes. As such, inhibition of STAT5 by a variety of mechanisms can rapidly induce apoptosis in certain lymphoid tumor cells, suggesting that it and its target genes represent therapeutic targets to control certain lymphoid diseases. To search for these molecules we aligned IL-2 regulated genes detected by Affymetrix gene expression microarrays with the STAT5 cistrome identified by chip-on-ChIP analysis in an IL-2-dependent human leukemia cell line, Kit225. Select overlapping genes were then validated using qRTPCR medium-throughput arrays in human PHA-activated PBMCs. Of 19 putative genes, one key regulator of T cell receptor signaling, PDE4B, was identified as a novel target, which was readily up-regulated at the protein level (3 h) in IL-2 stimulated, activated human PBMCs. Surprisingly, only purified CD8+ primary T-cells expressed PDE4B, but not CD4+ cells. Moreover, PDE4B was found to be highly expressed in CD4+ lymphoid cancer cells, which suggests that it may represent a physiological role unique to the CD8+ and lymphoid cancer cells and thus might represent a target for pharmaceutical intervention for certain lymphoid diseases.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "DRAK2 specifically interacted with TbRI (Figure 1B). Although subcellular localization of DAPK family members is dependent on the cell type, only DRAK2 is known to localize to both the cytosol and the nucleus (McGargill et al., 2004). Next, we examined the subcellular distribution of DRAK2 and TbRI in HeLa cells. "
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    ABSTRACT: TGF-β1 is a multifunctional cytokine that mediates diverse biological processes. However, the mechanisms by which the intracellular signals of TGF-β1 are terminated are not well understood. Here, we demonstrate that DRAK2 serves as a TGF-β1-inducible antagonist of TGF-β signaling. TGF-β1 stimulation rapidly induces DRAK2 expression and enhances endogenous interaction of the type I TGF-β receptor with DRAK2, thereby blocking R-Smads recruitment. Depletion of DRAK2 expression markedly augmented the intensity and the extent of TGF-β1 responses. Furthermore, a high level of DRAK2 expression was observed in basal-like and HER2-enriched breast tumors and cell lines, and depletion of DRAK2 expression suppressed the tumorigenic ability of breast cancer cells. Thus, these studies define a function for DRAK2 as an intrinsic intracellular antagonist participating in the negative feedback loop to control TGF-β1 responses, and aberrant expression of DRAK2 increases tumorigenic potential, in part, through the inhibition of TGF-β1 tumor suppressor activity.
    Preview · Article · Nov 2012 · Cell Reports
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