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J. Biol. Chem., Vol. 281, Issue 29, 19985-19994, July 21, 2006

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Cytohesin Binder and Regulator Augments T Cell Receptor-induced Nuclear Factor of Activated T Cells·AP-1 Activation through Regulation of the JNK Pathway^*

Qian Chen, Alan Coffey, Sylvain G. Bourgoin, and Massimo Gadina¹

From the Division of Infection and Immunity, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7BL, United Kingdom and Centre de Recherche en Rhumatologie et Immunologie, Université Laval, Sainte-Foy, Québec G1V 4G2, Canada

Cytohesin binder and regulator (Cybr; also known as CYTIP, CASP, and PSCDBP) is a cytokine-induced gene preferentially expressed in hematopoietic tissues and in T helper 1 cells. Cybr protein associates with members of the cytohesin family, which are known ADP-ribosylation factors-GDP/GTP exchange factors, and its functions appear to regulate lymphocyte adhesion and cell-cell contact. Here we show that Cybr mRNA and protein levels are increased upon T cell receptor engagement. Cybr expression then influences T cell receptor-dependent signaling events, such as nuclear factor of activated T cells and AP-1 transcriptional activity. In addition, expression of Cybr results in increased T cell receptor-mediated activation of the Rho/Rac exchange factor Vav and of the JNK-p38 MAPK signaling pathway. The effects of Cybr on nuclear factor of activated T cells and AP-1 are dependent on MAPK activation, and enhanced activation of this cascade results in cooperation between the two transcription factors in the regulation of gene expression. These findings provide the first evidence that the adaptor protein Cybr not only regulates lymphocyte adhesion and cell-cell interaction but also contributes to the regulation of the signaling cascade and of the genetic program downstream of the T cell receptor.

Received for publication, February 21, 2006 , and in revised form, April 20, 2006.

^* This work was supported by the Biotechnology and Biological Sciences Research Council (Project BB/C005090/1). 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 should be addressed: Whitla Medical Bldg., Rm. 222, 97 Lisburn Rd., Belfast BT9 7BL, Northern Ireland, UK. Tel.: 44-28-90972206; Fax: 44-28-90325839; E-mail: m.g.gadina{at}qub.ac.uk.

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