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J. Biol. Chem., Vol. 281, Issue 19, 13743-13750, May 12, 2006

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Regulation and Function of SKAP-55 Non-canonical Motif Binding to the SH3c Domain of Adhesion and Degranulation-promoting Adaptor Protein^*

Jonathan S. Duke-Cohan¹, Hyun Kang, Hebin Liu^¶, and Christopher E. Rudd^¶2

From the Department of Medical Oncology and Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Departments of Medicine and Pathology, Harvard Medical School, Boston, Massachusetts 02115 and the ^¶Molecular Immunology Section, Department of Immunology, Division of Investigative Sciences, Division of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 ONN, United Kingdom

The immune cell adaptor adhesion and degranulation promoting adaptor protein (ADAP) and its binding to T-cell adaptor Src kinase-associated protein of 55 kDa (SKAP-55) play a key role in the modulation of T-cell adhesion. While primary binding occurs via SKAP-55 SH3 domain binding to a proline-rich region in ADAP, a second interaction occurs between the ADAP C-terminal SH3 domain (ADAP-SH3c) and a non-canonical RKXXY²⁹⁴XXY²⁹⁷ motif in SKAP-55. Increasing numbers of non-canonical SH3 domain binding motifs have been identified in a number of biological systems. The presence of tyrosine residues in the SKAP-55 RKXXY²⁹⁴XXY²⁹⁷ motif suggested that phosphorylation might influence this unusual SH3 domain interaction. Here, we show that the Src kinase p59^fyn can induce the in vivo phosphorylation of the motif, and this event blocks ADAP-SH3c domain binding to the peptide motif. The importance of tyrosine phosphorylation was confirmed by plasmon resonance interaction analysis showing that phosphorylation of Tyr²⁹⁴ residue plays a central role in mediating dissociation, whereas phosphorylation of the second Tyr²⁹⁷ had no effect. Although loss of this secondary interaction did not result in the disruption of the complex, the Y294F mutation blocked T-cell receptor-induced up-regulation of lymphocyte function-associated antigen-1-mediated adhesion to intercellular adhesion molecule-1 and interleukin-2 promoter activity. Our findings identify a RKXXY²⁹⁴ motif in SKAP-55 that mediates unique ADAP SH3c domain binding and is needed for LFA-1-mediated adhesion and cytokine production.

Received for publication, August 9, 2005 , and in revised form, December 27, 2005.

^* This work was supported by the Wellcome Trust (Principal Research Fellowship) (to C. E. R.) and a Barr Program Award in Innovative and Basic Cancer Research (to J. S. D.-C.). 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 To whom correspondence may be addressed: Tel.: 617-632-3122; Fax: 617-632-3160; E-mail: jonathan_duke-cohan{at}dfci.harvard.edu.

² To whom correspondence may be addressed: Tel.: 44-(0)20-8383-8421; Fax: 44-(0)20-8383-8434; E-mail: c.rudd{at}imperial.ac.uk.

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