The Adaptor Protein 3BP2 Binds Human CD244 and Links this Receptor to Vav Signaling, ERK Activation, and NK Cell Killing

Saborit-Villarroya, Ifigènia; Valle, Juana M. Del; Romero, Xavier; Esplugues, Enric; Lauzurica, Pilar; Engel, Pablo; Martı́n, Margarita

doi:10.4049/jimmunol.175.7.4226

Cited by 43 publications

(41 citation statements)

References 45 publications

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“…53,54 Recently the adaptor protein 3BP2 was shown to recruit Vav1. 55 The interaction between Rab-27A and Vav1 is not characterized yet. It would be interesting to examine potential abilities of Vav1 to induce Rab-27A targets, which would explain the ability to bypass Rab-27A in exocytosis.…”

Section: Discussionmentioning

confidence: 99%

NK cytotoxicity mediated by CD16 but not by NKp30 is functional in Griscelli syndrome

Gazit

Aker

Elboim

et al. 2007

Blood

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Griscelli syndrome (GS) type 2 is an autosomal recessive disorder represented by pigment dilution and impaired cytotoxic T lymphocyte (CTL) activity. NK activity has been scarcely investigated in GS patients. Here, we describe a new patient, possessing a hemophagocytic syndrome with a homozygous Q118X nonsense RAB27A mutation. Single specific primerpolymerase chain reaction (SSP-PCR) was developed based on this mutation and is currently used in prenatal genetic analysis. As expected, CTLs in the patient are not functional and NK cytotoxicity against K562 or 721.221 cells is diminished. Surprisingly, however, we demonstrate that CD16-mediated killing is intact in this patient and is therefore RAB27A independent, whereas NKp30-mediated killing is impaired and is therefore RAB27A dependent. We further analyzed the signaling pathways of these 2 receptors and demonstrated phosphorylation of Vav1 after CD16 activation but not after NKp30 engagement. Thus, we identify a novel homozygous mutation in the RAB27A gene of a new GS patient, observe for the first time that some activating NK receptors function in GS patients, and demonstrate a functional dichotomy in the killing mediated by these human NK-activating receptors. ( IntroductionNatural killer (NK) cells are the lymphocytes of innate immunity, able to identify and eliminate virus-infected and tumor cells without prior antigen stimulation. 1,2 In addition, secretion of cytokines by NK cells recruits and activates additional immune cells and modulates the adaptive immune response. 3,4 Unlike other lymphocytes, NK cells do not express any single rearranged receptor such as the T-or B-cell receptors, but rather use a limited number of activating receptors. 5,6 The major human NK-activating receptors are NKp30, NKp44, NKp46, NKG2D, and the Fc␥RIIIA receptor CD16. 2,7 Engagement of NK lysis receptors leads to cytoskeleton reorganization, translocation of lytic granules, and directed exocytosis to facilitate the final step of killing. The precise understanding of signal transduction pathways of these receptors is therefore crucial for our basic understanding of how NK cells function.Griscelli syndrome (GS) was first described by Claude Griscelli et al, 8 who described 2 patients with a distinctive silver-gray hair color and impaired immune activity. Since the first description, heterogeneity in clinical manifestations of the syndrome has been recognized in about 100 patients reported so far. Genetic studies found mutations in MYO5A, RAB27A, or MLPH, and patients were thereafter categorized as GS type 1, 2, or 3, respectively. 9-11 The abnormal pigmentation is a common feature of all of these patients and immunologic impairments are associated with RAB27A mutations, whereas MYO5A and MLPH have redundant role in lymphoid cells. 12 Despite the apparent immunodeficiency, the major clinical difficulty is not an overwhelming infection, but rather a fatal hemophagocytic syndrome caused by inappropriate and excessive lymphoid-cell activation and cytokine release often triggered...

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Section: Discussionmentioning

confidence: 99%

NK cytotoxicity mediated by CD16 but not by NKp30 is functional in Griscelli syndrome

Gazit

Aker

Elboim

et al. 2007

Blood

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“…The following biotinylated anti-human mAbs were produced in our laboratory: CD84 (CD84.1.21), CD150 (SLAM.4), CD229 (HLy9.1.84) and CD244 (2B4.69) [9][10][11][12]. Biotinylated anti-human CD48 (99A) was provided by R. Vilella (Hospital Clinic, Barcelona, Spain) and CD150 mAbs (clones A12, 1B12, 10F5, 11G2, and 5G4) by Cox Terhorst (Harvard Medical School, Cambridge, MA, USA).…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

Differential expression of CD150 (SLAM) family receptors by human hematopoietic stem and progenitor cells

Sintes

Romero

Marı́n³

et al. 2008

Experimental Hematology

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Objectives-Human hematopoietic stem cell (HSC)-containing grafts are most commonly used to treat various blood diseases, including leukemias and autoimmune disorders. CD150 (SLAM) family receptors have recently been shown to be differentially expressed by mouse HSC and progenitor cells. Members of the CD150 family are key regulators of leukocyte activation and differentiation. The goal of the present study is to analyze the expression patterns of the CD150 receptors CD48, CD84, CD150 (SLAM), CD229 (Ly9), and CD244 (2B4) on the different sources of human hematopoietic stem and progenitor cells.Materials and Methods-Expression of CD150 receptors was analyzed on human mobilized peripheral blood CD133 + -isolated cells and CD34 + bone marrow (BM) and umbilical cord blood (CB) cells using multicolor flow cytometry.Results-CD244 was present on most CD133 + Lin − -mobilized cells and CD34 + Lin − BM and CB cells, including virtually all CD38 − Lin − primitive progenitor cells. CD48 had a restricted expression pattern on CD133 + Lin − CD38 − cells, while its levels were significantly higher in CD34 + Lin − BM and CB cells. In addition, CD84 was present on a significant number of CD133 + Lin − cells, but only on a small fraction of CD133 + Lin − CD38 − peripheral blood mobilized cells. In contrast, CD84 was expressed on practically all CD34 + Lin − BM cells. No CD150 expression was observed in mobilized peripheral blood CD133 + Lin − or CD34 + Lin − BM and CB cells. Furthermore, only a small fraction of CD34 + Lin − BM and CB cells expressed CD229.Conclusions-Our results show that CD150 family molecules are present on human hematopoietic stem and progenitor cells and that their expression patterns differ between humans and mice.Hematopoietic stem cells (HSCs) are a rare cell type found mainly in the bone marrow (BM), which have the capacity to self-renew and differentiate into all blood cell lineages [1].

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“…Human PBMC were obtained from heparinized venous blood of healthy donors by Ficoll-Hypaque gradient centrifugation. Human NK cells were isolated and cultured as described (13).…”

Section: Cells and Absmentioning

confidence: 99%

Molecular and Functional Characterization of CD300b, a New Activating Immunoglobulin Receptor Able to Transduce Signals through Two Different Pathways

Martínez-Barriocanal

Sayós

2006

The Journal of Immunology

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In this study, we describe the characterization of human CD300b, a novel member of the CMRF-35/immune receptor expressed by myeloid cell (IREM) multigene family of immune receptors. Immune receptor expressed by myeloid cell-3 cDNA was cloned from a PHA-activated PBMC library and RT-PCR revealed the gene to be expressed preferentially in cells of myeloid origin. The CD300b cDNA open reading frame encodes a 201-aa type I protein composed of a single extracellular Ig V-type domain followed by a transmembrane region containing a positively charged residue (lysine) which is a common feature among receptors that associate with activating adaptor proteins. Indeed, CD300b was able to associate with DNAX-activating protein of 12 kDa (DAP-12) and deliver different activating signals through this ITAM-based adaptor. Unusually for an activating receptor, the 29-aa cytoplasmic tail of CD300b contains a tyrosine-based motif that, upon c-Fyn phosphorylation, became a docking site for the intracellular signaling mediator growth factor receptor-bound protein 2. Moreover, in the absence of DAP-12, CD300b was able to activate NFAT/AP-1-dependent transcriptional activity in RBL-2H3 cells. This activity could be abolished only by mutating both the cytoplasmic tyrosine and the transmembrane lysine. Our data suggest the existence of an unidentified molecule capable of interacting with CD300b through a charged residue of the transmembrane region and allowing receptor signaling independent of DAP-12. Therefore, CD300b defines a nonclassical Ig receptor able to trigger signals by coupling distinct mediators and thus initiating different signaling pathways.

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The Adaptor Protein 3BP2 Binds Human CD244 and Links this Receptor to Vav Signaling, ERK Activation, and NK Cell Killing

Cited by 43 publications

References 45 publications

NK cytotoxicity mediated by CD16 but not by NKp30 is functional in Griscelli syndrome

NK cytotoxicity mediated by CD16 but not by NKp30 is functional in Griscelli syndrome

Differential expression of CD150 (SLAM) family receptors by human hematopoietic stem and progenitor cells

Molecular and Functional Characterization of CD300b, a New Activating Immunoglobulin Receptor Able to Transduce Signals through Two Different Pathways

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