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 Blood, 1 May 2006, Vol. 107, No. 9, pp. 3647-3655.
Prepublished online as a Blood First Edition Paper on January 26, 2006; DOI 10.1182/blood-2005-10-4102.

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Submitted October 17, 2005
Accepted December 27, 2005

Dual function for the adaptor MIST in IFN-{gamma} production by NK and CD4+NKT cells regulated by the Src-kinase Fgr

Hiroki Sasanuma, Akiko Tatsuno, Shinya Hidano, Keiko Ohshima, Yumi Matsuzaki, Katsuhiko Hayashi, Clifford A Lowell, Daisuke Kitamura, and Ryo Goitsuka*

Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba, Japan
Department of Physiology, Keio University School of Medicine, Shinjyuku, Tokyo, Japan
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA

* Corresponding author; email: ryogoi{at}rs.noda.tus.ac.jp.

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 two 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.


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S. Hidano, H. Sasanuma, K. Ohshima, K.-i. Seino, L. Kumar, K. Hayashi, M. Hikida, T. Kurosaki, M. Taniguchi, R. S. Geha, et al.
Distinct regulatory functions of SLP-76 and MIST in NK cell cytotoxicity and IFN-{gamma} production
Int. Immunol., March 1, 2008; 20(3): 345 - 352.
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