Regulation of NK Cell Function by Vav-family Proteins

Summary

Principal Investigator: WOJCIECH A SWAT
Abstract: Vav proteins are guanine nucleotide exchange factors and molecular adaptors that play a key role in signal transduction of lymphocyte antigen receptors. Several recent studies have also implicated Vav1 in natural killer (NK) cell-mediated cytotoxicity of tumor cells. However, whether Vav1 effects all NK cell activating pathways is not known, and it is possible that other Vav family molecules are involved in NK cell triggering. NK cells recognize tumor or virally-infected cells through multiple activating receptors with diverse structures, specificities and signaling adaptors. The activating NK cell receptor NKG2D recognizes endogenous major histocompatibility complex (MHC) class I-related molecules expressed at high levels primarily in virally infected and tumor cells while Ly49H mediates selective recognition of m157, a murine cytomegalovirus (MCMV)-encoded class I-like molecule that is expressed on infected cells. Both NKG2D and Ly49H deliver stimulatory signals which trigger secretion of IFN-? and release of cytotoxic granules that contain perforin and granzymes. However, it is not know exactly how such stimulatory signals are transduced inside the NK cells. NKG2D and Ly49D/H lack cytoplasmic signaling elements and can deliver stimulatory signals only by associating with transmembrane adaptor proteins. Ly49D and Ly49H signal through DAP12 (also called KARAP) which contains immunoreceptor tyrosine-based activation motifs (ITAM) that are phosphorylated and function as docking sites for Syk and ZAP70 protein tyrosine kinases. In contrast, NKG2D signals through DAP10, a unique adapter that contains a YxNM motif which recruits phosphatidyl inositol 3-kinase (PI3-K) and Grb-2. As part of our preliminary studies for this proposal we generated mice lacking the individual, or all, Vavfamily proteins and began to examine the potential contribution of these proteins to NK cell cytotoxicity. Intriguingly, these data indicate that Vav is essential for DAP10- but not for DAP12-mediated natural cytotoxicity. Thus, these data suggest a new paradigm regarding the utilization of Vav in activation of natural cytotoxicity downstream of NK cell surface receptors associated with non-ITAM- vs. ITAM-containing adaptors. Here, we propose to use several in vitro and in vivo approaches to determine Vav mechanism in NK cell function and development of natural cytotoxicity against virally-infected and tumor cells.
Funding Period: 2005-03-01 - 2008-02-28
more information: NIH RePORT

Top Publications

  1. ncbi Vav1 controls DAP10-mediated natural cytotoxicity by regulating actin and microtubule dynamics
    Daniel B Graham
    Department of Pathology and Immunology, Washington University School of Medicine and Siteman Cancer Center, 660 South Euclid Avenue, St Louis, MO 63110, USA
    J Immunol 177:2349-55. 2006
  2. pmc Vav/Phospholipase Cgamma2-mediated control of a neutrophil-dependent murine model of rheumatoid arthritis
    Viviana Cremasco
    Washington University School of Medicine, St Louis, Missouri 63110, USA
    Arthritis Rheum 58:2712-22. 2008
  3. pmc Vav proteins control MyD88-dependent oxidative burst
    Ana V Miletic
    Department of Pathology and Immunology, Washington University School of Medicine and Siteman Cancer Center, 660 S Euclid Avenue, St Louis, MO 63110, USA
    Blood 109:3360-8. 2007
  4. pmc Discs-large homolog 1 regulates smooth muscle orientation in the mouse ureter
    Zhen X Mahoney
    Department of Internal Medicine, Renal Division, Washington University School of Medicine, St Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 103:19872-7. 2006

Detail Information

Publications4

  1. ncbi Vav1 controls DAP10-mediated natural cytotoxicity by regulating actin and microtubule dynamics
    Daniel B Graham
    Department of Pathology and Immunology, Washington University School of Medicine and Siteman Cancer Center, 660 South Euclid Avenue, St Louis, MO 63110, USA
    J Immunol 177:2349-55. 2006
    ..Based on these findings, we propose a novel model of ITAM-independent signaling by Vav downstream of DAP10 in NK cells...
  2. pmc Vav/Phospholipase Cgamma2-mediated control of a neutrophil-dependent murine model of rheumatoid arthritis
    Viviana Cremasco
    Washington University School of Medicine, St Louis, Missouri 63110, USA
    Arthritis Rheum 58:2712-22. 2008
    ..The aim of this study was to test the hypothesis that Vav and phospholipase Cgamma2 (PLCgamma2), two molecules involved in integrin signaling, are required for arthritis generation and neutrophil activation in a mouse model of arthritis...
  3. pmc Vav proteins control MyD88-dependent oxidative burst
    Ana V Miletic
    Department of Pathology and Immunology, Washington University School of Medicine and Siteman Cancer Center, 660 S Euclid Avenue, St Louis, MO 63110, USA
    Blood 109:3360-8. 2007
    ..Thus, our data indicate that Vav specifically transduces a subset of signals emanating from MyD88...
  4. pmc Discs-large homolog 1 regulates smooth muscle orientation in the mouse ureter
    Zhen X Mahoney
    Department of Internal Medicine, Renal Division, Washington University School of Medicine, St Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 103:19872-7. 2006
    ..Our results suggest that (i) besides its well documented role in regulating epithelial polarity, Dlgh1 also regulates smooth muscle orientation, and (ii) human DLG1 mutations may contribute to hereditary forms of hydronephrosis...