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Molecular and Cellular Biology, August 2006, p. 5559-5568, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00357-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Association between SAP and FynT: Inducible SH3 Domain-Mediated Interaction Controlled by Engagement of the SLAM Receptor

Riyan Chen,1 Sylvain Latour,1,2 Xiaochu Shi,1 and André Veillette1,3,4*

Laboratory of Molecular Oncology, Clinical Research Institute of Montreal, Montréal, Québec, Canada,1 Unité INSERM U768, Hôpital Necker Enfants-Malades, Paris, France,2 Department of Medicine, University of Montréal, Montréal, Québec, Canada,3 Department of Medicine, McGill University, Montréal, Québec, Canada4

Received 27 February 2006/ Returned for modification 12 April 2006/ Accepted 22 May 2006

SAP is an intracellular adaptor molecule composed almost exclusively of an SH2 domain. It is mutated in patients with X-linked lymphoproliferative disease, a human immunodeficiency. Several immune abnormalities were also identified in SAP-deficient mice. By way of its SH2 domain, SAP interacts with tyrosine-based motifs in the cytoplasmic domain of SLAM family receptors. SAP promotes SLAM family receptor-induced protein tyrosine phosphorylation, due to its capacity to recruit the Src-related kinase FynT. This unusual property relies on the existence of a second binding surface in the SAP SH2 domain, centered on arginine 78 of SAP, that binds directly to the FynT SH3 domain. Herein, we wanted to further understand the mechanisms controlling the interaction between SLAM-SAP and FynT. Our experiments showed that, unlike conventional associations mediated by SH3 domains, the interaction of the FynT SH3 domain with SLAM-SAP was strictly inducible. It was absolutely dependent on engagement of SLAM by extracellular ligands. We obtained evidence that this inducibility was not due to increased binding of SLAM to SAP following SLAM engagement. Furthermore, it could occur independently of any appreciable SLAM-dependent biochemical signal. In fact, our data indicated that the induced association of the FynT SH3 domain with SLAM-SAP was triggered by a change in the conformation of SLAM-associated SAP caused by SLAM engagement. Together, these data elucidate further the events initiating SLAM-SAP signaling in immune cells. Moreover, they identify a strictly inducible interaction mediated by an SH3 domain.

* Corresponding author. Mailing address: IRCM, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7. Phone: (514) 987-5561. Fax: (514) 987-5562. E-mail: veillea{at}ircm.qc.ca.

Molecular and Cellular Biology, August 2006, p. 5559-5568, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00357-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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