International Immunology Advance Access originally published online on April 13, 2004
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International Immunology, Vol. 16, No. 5, pp. 727-736,
May 2004
© 2004 Japanese Society for Immunology
SAP increases FynT kinase activity and is required for phosphorylation of SLAM and Ly9
1 Division of Immunology, Beth Israel Deaconess Medical Center and 2 Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA 3 Division of Hematology and Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA 4 Present address: Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA 5 Present address: Institute of Immunology, University of Debrecen, H-4012, Hungary
Correspondence to: C. Terhorst or M. Simarro; E-mail: terhorst{at}caregroup.harvard.edu or msimarro{at}rics.bwh.harvard.edu
Transmitting editor: T. Tedder
The free Src homology 2 (SH2) domain protein SAP, encoded by the X-linked lymphoproliferative disease gene SH2D1A, controls signal transduction initiated by engagement of the SLAM-related receptors in T and NK cells. Here we demonstrate that SAP is required for phosphorylation of both SLAM and Ly9 in thymocytes and peripheral T cells. Furthermore, in vitro protein interaction studies and yeast two-hybrid analyses indicated that SAP binds directly to FynT and Lck. While SAP bound to both the SH3 domain and to the kinase domain of FynT, SAP bound solely to the kinase domain of Lck. The existence of a strong interaction between SAP and the SH3 domain of FynT prompted us to study the role of SAP in modulating the activity of FynT. In vitro addition of SAP to the autoinhibited form of FynT caused a large increase in FynT catalytic activity. By contrast, the SAP mutant R78E, which is unable to bind to the FynT SH3 domain, did not increase FynT activity and also displayed a reduced adaptor function upon transfection into T cells. Our results demonstrate that SAP is an adaptor that bridges SLAM and Ly9 with Src-like protein tyrosine kinases (PTKs), and has the ability to activate FynT.
Keywords: signal transduction, Src, T-lymphocyte, X-linked lymphoproliferative disease
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