Nature Immunology
2, 681 - 690 (2001)
doi:10.1038/90615
Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene productSylvain Latour1, 2, 3, Gerald Gish4, Cheryl D. Helgason5, R. Keith Humphries5, Tony Pawson4
& André Veillette1, 2, 61
Laboratory of Molecular Oncology, IRCM, 110 Pine Ave. West, Montréal, Québec, Canada H2W 1R7. 2
McGill Cancer Centre, McGill University, Montréal, Québec, Canada H3G 1Y6. 3
Unité INSERM U429, Hôpital Necker-Enfants Malades, Paris, France. 4
The Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5. 5
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada V5Z 1L3. 6
Departments of Biochemistry, Medicine and Microbiology and Immunology, McGill University, Montréal, Québec, Canada H3G 1Y6.
Correspondence should be addressed to André Veillette veillea@ircm.qc.caSignaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is a short intracellular molecule that is mutated in humans with X-linked lymphoproliferative (XLP) disease. Although the exact role and mechanism of action of SAP are not known, it has the capacity to interact with the cytoplasmic region of SLAM and other related immune cell receptors. As SAP is composed almost exclusively of a Src homology 2 (SH2) domain, it has been proposed that it functions as a natural blocker of SH2 domain−mediated interactions. We report here that the SLAM receptor is capable of triggering a protein tyrosine phosphorylation signal in T cells via a mechanism that is strictly dependent on SAP expression. This signal involves the SH2 domain−containing inositol phosphatase (SHIP); the adaptor molecules Dok2, Dok1 and Shc; and Ras GTPase−activating protein RasGAP. SAP is essential for this pathway because it facilitates the selective recruitment and activation of the Src-related protein tyrosine kinase FynT. We also show that signaling via the SLAM-SAP pathway in an established T cell line can alter the profile of cytokine production during T cell activation. These findings identify a mechanism by which a putative adaptor molecule is required for receptor-mediated signaling events in the immune system. They also provide insights into the pathophysiology of a severe human lymphoproliferative disease.
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