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J. Biol. Chem., Vol. 282, Issue 5, 2937-2946, February 2, 2007

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Dual Role of SLP-76 in Mediating T Cell Receptor-induced Activation of Phospholipase C-1^*

Dvora Beach, Ronnie Gonen, Yaron Bogin, Ilona G. Reischl¹, and Deborah Yablonski²

From the Rappaport Family Institute for Research in the Medical Sciences, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel and the Laboratory of Immunobiology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, National Institutes of Health Campus, Bethesda, Maryland 20892

Phospholipase C-1 (PLC-1) activation depends on a heterotrimeric complex of adaptor proteins composed of LAT, Gads, and SLP-76. Upon T cell receptor stimulation, a portion of PLC-1 is recruited to a detergent-resistant membrane fraction known as the glycosphingolipid-enriched membrane microdomains (GEMs), or lipid rafts, to which LAT is constitutively localized. In addition to LAT, PLC-1 GEM recruitment depended on SLP-76, and, in particular, required the Gads-binding domain of SLP-76. The N-terminal tyrosine phosphorylation sites and P-I region of SLP-76 were not required for PLC-1 GEM recruitment, but were required for PLC-1 phosphorylation at Tyr⁷⁸³. Thus, GEM recruitment can be insufficient for full activation of PLC-1 in the absence of a second SLP-76-mediated event. Indeed, a GEM-targeted derivative of PLC-1 depended on SLP-76 for T cell receptor-induced phosphorylation at Tyr⁷⁸³ and subsequent NFAT activation. On a biochemical level, SLP-76 inducibly associated with both Vav and catalytically active ITK, which efficiently phosphorylated a PLC-1 fragment at Tyr⁷⁸³ in vitro. Both associations were disrupted upon mutation of the N-terminal tyrosine phosphorylation sites of SLP-76. The P-I region deletion disrupted Vav association and reduced SLP-76-associated kinase activity. A smaller deletion within the P-I region, which does not impair PLC-1 activation, did not impair the association with Vav, but reduced SLP-76-associated kinase activity. These results provide new insight into the multiple roles of SLP-76 and the functional importance of its interactions with other signaling proteins.

Received for publication, July 14, 2006 , and in revised form, November 27, 2006.

^* This work was supported by the Rappaport Family Institute for Research in the Medical Sciences and by the Technion V.P.R. Research Fund-Charles Krown Research Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: AGES PharmMed, A-1030 Vienna, Austria.

² To whom correspondence should be addressed: Rappaport Faculty of Medicine, Technion-Israel Inst. of Technology, P. O. Box 9649 Bat Galim, Haifa 31096, Israel. Tel.: 972-4-829-5393; Fax: 972-4-829-5255; E-mail: debya{at}tx.technion.ac.il.

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