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J. Biol. Chem., Vol. 282, Issue 39, 29059-29066, September 28, 2007

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SLP-65 Signal Transduction Requires Src Homology 2 domain-mediated Membrane Anchoring and a Kinase-independent Adaptor Function of Syk^*

From the Georg August University of Göttingen, Institute of Cellular & Molecular Immunology, Humboldtallee 34, 37073 Göttingen, Germany

The family of SLPs (Src homology 2 domain-containing leukocyte adaptor proteins) are cytoplasmic signal effectors of lymphocyte antigen receptors. A main function of SLP is to orchestrate the assembly of Ca²⁺-mobilizing enzymes at the inner leaflet of the plasma membrane. For this purpose, SLP-76 in T cells utilizes the transmembrane adaptor LAT, but the mechanism of SLP-65 membrane anchoring in B cells remains an enigma. We now employed two genetic reconstitution systems to unravel structural requirements of SLP-65 for the initiation of Ca²⁺ mobilization and subsequent activation of gene transcription. First, mutational analysis of SLP-65 in DT40 B cells revealed that its C-terminal Src homology 2 domain controls efficient tyrosine phosphorylation by the kinase Syk, plasma membrane recruitment, as well as downstream signaling to NFAT activation. Second, we dissected these processes by expressing SLP-65 in SLP-76-deficient T cells and found that a kinase-independent adaptor function of Syk is required to link phosphorylated SLP-65 to Ca²⁺ mobilization. These approaches unmask a mechanistic complexity of SLP-65 activation and coupling to signaling cascades in that Syk is upstream as well as downstream of SLP-65. Moreover, membrane anchoring of the SLP-65-assembled Ca²⁺ initiation complex, which appears to be fundamentally different from that of closely related SLP-76, does not necessarily involve a B cell-specific component.

Received for publication, May 16, 2007 , and in revised form, July 10, 2007.

^* This work is supported by Deutsche Forschungsgemeinschaft Grant FOR 521 and the program for new and emerging science and technology (NEST) of the European Union through grant HYBLIB. 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: Georg August University of Göttingen, Institute of Cellular & Molecular Immunology, Humboldtallee 34, 37073 Göttingen, Germany. Tel.: 49-551-39-5812; Fax: 49-551-39-5843; E-mail: jwienan{at}uni-goettingen.de.

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