Dual function for the adaptor MIST in IFN-gamma production by NK and CD4+NKT cells regulated by the Src kinase Fgr.
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.
Sasanuma
Hiroki
H
Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.
Tatsuno
Akiko
A
Hidano
Shinya
S
Ohshima
Keiko
K
Matsuzaki
Yumi
Y
Hayashi
Katsuhiko
K
Lowell
Clifford A
CA
Kitamura
Daisuke
D
Goitsuka
Ryo
R
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*
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