Cutting Edge: Defective NK Cell Activation in X-Linked Lymphoproliferative Disease

Benoît, Loralyn A.; Wang, Xiaoxia; Pabst, Henry F.; Dutz, Jan P.; Tan, Rusung

doi:10.4049/jimmunol.165.7.3549

Cited by 142 publications

(115 citation statements)

References 33 publications

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“…In the absence of SAP, the functions of the SLAM family would be compromised or perhaps qualitatively modified, explaining the pleiotropic consequences of SAP deficiency in humans and mice. In agreement with this idea, it has already been shown that the ability of 2B4 and NTB-A to trigger cytotoxicity is drastically reduced in NK cell cultures isolated from XLP patients [13][14][15][16][17][18]. Furthermore, it is plausible that the late CD4 + T cell help defect observed in SAP-deficient mice (that may also explain the hypogammaglobulinemia seen in XLP patients) is the effect of altered functions of SLAM and, perhaps, NTB-A, Ly-9 and CD84.…”

Section: Resultssupporting

confidence: 58%

Mini‐review SAP: a molecular switch regulating the immune response through a unique signaling mechanism

Veillette

2003

Eur J Immunol

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Section: Resultssupporting

confidence: 58%

Mini‐review SAP: a molecular switch regulating the immune response through a unique signaling mechanism

Veillette

2003

Eur J Immunol

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“…Ligationinduced phosphorylation of 2B4 recruits intracellular proteins that include PI3K and SLAM-associated protein (SAP) 3 to its cytoplasmic domain, thus initiating a signaling cascade, substantial elements of which are unknown (6, 10 -14). Mutations of SAP, an intracellular adaptor protein containing a single Src homology SH2 domain, are associated with the fatal disorder X-linked lymphoproliferative (XLP) disease (15)(16)(17) and NK cells from XLP patients lack normal function when stimulated through 2B4 (10,12,13,18,19). Although the precise physiologic functions of SAP in NK cells remain unknown, it is thought that this protein competes with SH2 protein tyrosine phosphatases for binding to tyrosinephosphorylated 2B4 thus preventing the delivery of negative signals through 2B4 (16).…”

Section: Role For Glycogen Synthase Kinase-3 In Nk Cellmentioning

confidence: 99%

Role for Glycogen Synthase Kinase-3 in NK Cell Cytotoxicity and X-Linked Lymphoproliferative Disease

Aoukaty

Tan

2005

The Journal of Immunology

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NK cells from individuals with X-linked lymphoproliferative (XLP) disease exhibit functional defects when stimulated through the NK receptor, 2B4 (CD244). These defects are likely a consequence of aberrant intracellular signaling initiated by mutations of the adaptor molecule SLAM-associated protein. In this report, we show that NK cells from individuals with XLP but not healthy individuals fail to phosphorylate and thereby inactivate glycogen synthase kinase-3 (GSK-3) following 2B4 stimulation. Lack of GSK-3 phosphorylation prevented the accumulation of the transcriptional coactivator β-catenin in the cytoplasm and its subsequent translocation to the nucleus. Potential signaling pathways leading from 2B4 stimulation to GSK-3 phosphorylation were also investigated. Ligation of 2B4 resulted in the phosphorylation of the guanine nucleotide exchange factor, Vav-1, and subsequent activation of the GTP-binding protein Rac-1 (but not Ras) and the serine-threonine kinase Raf-1 in healthy but not XLP-derived NK cells. In addition, the activity of MEK-2 (but not MEK-1) was up-regulated, and Erk1/2 was phosphorylated in normal NK cells but not those from an individual with XLP suggesting that these proteins relay SLAM-associated protein-dependent signals from 2B4. Finally, inactivation of GSK-3 using a specific inhibitor of GSK-3β increased the cytotoxicity and cytokine secretion of both healthy and XLP NK cells. These data indicate that the signaling of 2B4 in NK cells is mediated by GSK-3 and β-catenin, possibly through a signal transduction pathway that involves Vav-1, Rac-1, Raf-1, MEK-2, and Erk1/2 and that this pathway is aberrant in individuals with XLP.

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“…Although a good deal of information has been accumulated regarding the SAP recruitment of Fyn to SLAM-family receptors and the importance of the SAP-Fyn interaction in immune cell functions (12,18,26,27), little is known about the mechanism by which SAP initiates various signaling processes. Here, we identified another important family of signaling molecules including ␣PIX and ␤PIX, which interacted with SAP in T cells.…”

Section: Discussionmentioning

confidence: 99%

The X-linked lymphoproliferative disease gene product SAP associates with PAK-interacting exchange factor and participates in T cell activation

Tangye

Sun

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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SLAM (signaling lymphocyte activation molecule)-associated protein (SAP) is a Src homology 2 (SH2) domain-containing adaptor expressed in T cells and natural killer cells. Its essential role inimmune responses is underscored by the recent finding that mutations in SAP result in a rare but fatal X-linked lymphoproliferative disease (XLP). Although SAP is known to associate with SLAM-family receptors, the exact molecular mechanism by which SAP regulates lymphocyte signaling remains elusive. We here report that in T cells, SAP associates with the PAK-interacting exchange factor (PIX), a guanine nucleotide exchange factor (GEF) specific for Rac͞Cdc42 GTPases. Moreover, SAP, PIX, and an activated form of Cdc42 form a complex in mammalian cells. We demonstrate that the SAP-PIX interaction is specific and is mediated by the C-terminal region of the SAP SH2 domain and the PIX SH3 domain. We further show that SAP is required for the recruitment of PIX to the SLAM-family receptors. Interestingly, overexpression of SAP, but not its homolog EAT-2, leads to a synergistic activation of nuclear factor of activating T cells (NFAT) in combination with a calcium signal in T cells. This SAP-mediated activation appears to be receptor-dependent and can be blocked by a dominant negative form of PIX. Taken together, our data strongly suggest that, in addition to the known SAP-interacting kinase Fyn, PIX may be another key player in SAP-mediated T cell activation.nuclear factor of activating T cells (NFAT) ͉ Cdc42 ͉ 2B4 ͉ Fyn X -linked lymphoproliferative disease (XLP) is an inherited severe or fatal immune dysfunction generally triggered by infection with Epstein-Barr virus (EBV) (1). XLP patients often develop a lethal fulminant infectious mononucleosis after EBV infection. Some patients also develop progressive dysgammaglobulinemia, malignant lymphomas, or autoimmunity such as vasculitis (2-4). Several immune cell types have been shown to exhibit functional alterations in XLP, including CD4 ϩ T cells, CD8 ϩ T cells, natural killer cells, and B cells (3). In 1998, three groups identified the gene aberrant in XLP, named as SAP͞ SH2D1A͞DSHP (5-7). The human SLAM (signaling lymphocyte activation molecule)-associated protein (SAP) is comprised of 128 amino acids, of which residues 6-102 contribute to an N-terminal SH2 domain. Many experiments have shown that the SH2 domain of SAP preferentially recognize specific tyrosinebased motifs containing TxYxxV͞I that are present within the cytoplasmic tails of SLAM and its related receptors, including 2B4, CD84, Ly9, NTB-A, and CRACC (1,8,9). Because XLP patients lack functional SAP, it has been speculated that the phenotypes of XLP likely reflect perturbed signaling downstream of one or more of these receptors, ultimately resulting in abnormal immune responses.Given the severe clinical manifestations in XLP patients, recent efforts have been focused on elucidating the signaling mechanism by which SAP regulates in T and natural killer cells. It has been shown that SAP recruits a Src kinase Fyn to...

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Cutting Edge: Defective NK Cell Activation in X-Linked Lymphoproliferative Disease

Cited by 142 publications

References 33 publications

Mini‐review SAP: a molecular switch regulating the immune response through a unique signaling mechanism

Mini‐review SAP: a molecular switch regulating the immune response through a unique signaling mechanism

Role for Glycogen Synthase Kinase-3 in NK Cell Cytotoxicity and X-Linked Lymphoproliferative Disease

The X-linked lymphoproliferative disease gene product SAP associates with PAK-interacting exchange factor and participates in T cell activation

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