title: Dual function for the adaptor MIST in IFN-gamma production by NK and CD4+NKT cells regulated by the Src kinase Fgr.
abstract: Natural killer (NK) cells and NKT cells play critical early roles in host defense. Here we show that MIST, an adaptor protein belonging to the SLP-76 family, functions negatively in NK cells but positively in CD4(+)NKT cells. NK-cell receptor-mediated IFN-gamma production was enhanced in NK cells, whereas TCR- or NK-cell receptor-mediated cytokine production was reduced in CD4(+)NKT cells from MIST-deficient mice. These opposite effects of MIST paralleled the exclusive expression of the Src family kinase, Fgr, in NK cells between the 2 cell populations. We further demonstrated that interaction of MIST with Fgr, mediated by the C-terminal proline-rich region of MIST and the SH3 domain of Fgr, was required for the suppression of NK-cell receptor-induced IFN-gamma production. This functional interdependence of signaling molecules demonstrates a new mechanism by which adaptor proteins can act as molecular switches to control diverse responses in different cell populations.
authors.affiliation: Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasanuma
authors.forename: Akiko
authors.initials: A
authors.lastname: Tatsuno
authors.forename: Shinya
authors.initials: S
authors.lastname: Hidano
authors.forename: Keiko
authors.initials: K
authors.lastname: Ohshima
authors.forename: Yumi
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hayashi
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kitamura
authors.forename: Ryo
authors.initials: R
authors.lastname: Goitsuka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000503:physiopathology; D010641:Phenotype; D051966:Phospholipase C gamma / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018909:src Homology Domains; D019061:src-Family Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C488191:Clnk protein, mouse; D018076:DNA, Complementary; D011518:Proto-Oncogene Proteins; D007371:Interferon-gamma; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases; D051966:Phospholipase C gamma