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DAP12-mediated signal transduction in a natural killer cells - A dominant role for the Syk protein-tyrosine kinase

  1. Author:
    McVicar, D. W.
    Taylor, L. S.
    Gosselin, P.
    Willette-Brown, J.
    Mikhael, A. I.
    Geahlen, R. L.
    Nakamura, M. C.
    Linnemeyer, P.
    Seaman, W. E.
    Anderson, S. K.
    Ortaldo, J. R.
    Mason, L. H.

  2. Author Address

    McVicar DW NCI, Expt Immunol Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr,NIH Bldg 560,Room 31-93 Frederick, MD 21702 USA NCI, Expt Immunol Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr,NIH Frederick, MD 21702 USA NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr Frederick, MD 21702 USA Purdue Univ, Dept Med Chem & Mol Pharmacol W Lafayette, IN 47907 USA Univ Calif San Francisco, Dept Med San Francisco, CA 94143 USA Vet Adm Med Ctr San Francisco, CA 94121 USA
    1. Year: 1998
  2. Journal: Journal of Biological Chemistry
    1. 273
    2. 49
    3. Pages: 32934-32942
  4. Type of Article: Article
  1. Abstract:

    The murine Ly49 family contains nine genes in two subgroups: the inhibitory receptors (Ly49A, B, C, E, F, G2, and I) and the noninhibitory receptors (Ly49D and H), Unlike their inhibitory counterparts, Ly49D and H do not contain immunoreceptor tyrosine-based inhibitory motifs but associate with a recently described coreceptor, DAP12, to transmit positive signals to natural killer (NK) cells. DAP12 is also expressed in myeloid cells, but the receptors coupled to it there are unknown. Here we document the signaling pathways of the Ly49D/ DAP12 complex in NK cells. We show that ligation of Ly49D results in 1) tyrosine phosphorylation of several substrates, including phospholipase C gamma 1, Cbl, and p44/ p42 mitogen-activated protein kinase, and 2) calcium mobilization. Moreover, we demonstrate that although human DAP12 reportedly binds the SH2 domains of both Syk and Zap-70, ligation of Ly49D leads to activation of Syk but not Zap-70. Consistent with this observation, Ly49D/DAP12-mediated calcium mobilization is blocked by dominant negative Syk but not by catalytically inactive Zap-70. These data demonstrate the dependence of DAP12-coupled receptors on Syk and suggest that the outcome of Ly49D/DAP12 engagement mill be regulated by Cbl and culminate in the activation of transcription factors. [References: 63]

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