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J. Biol. Chem., Vol. 279, Issue 39, 40647-40652, September 24, 2004

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The ALX Src Homology 2 Domain Is Both Necessary and Sufficient to Inhibit T Cell receptor/CD28-mediated Up-regulation of RE/AP^*

Michael J. Shapiro, Penda Powell, Adanma Ndubuizu, Chima Nzerem, and Virginia Smith Shapiro

From the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Activation of naive T cells occurs when two signals are received. The first signal is received through the T cell antigen receptor (TCR), and a second costimulatory signal is primarily provided by CD28. We have recently identified a novel adaptor molecule, ALX, which is expressed exclusively in hematopoietic cells. ALX contains several sites for potential protein-protein interaction, including an Src homology 2 (SH2) domain, four PXXP polyproline sequences, and two likely sites of tyrosine phosphorylation. Overexpression of ALX inhibits the transcriptional activation of the interleukin 2 promoter during T cell activation, specifically affecting CD28-mediated activation of the RE/AP element of the interleukin 2 promoter. To understand how ALX functions downstream of CD28, we generated a panel of site-directed mutants as well as truncations in which potential protein-binding sites were mutated or absent. We found that the ALX SH2 domain is both necessary and sufficient to mediate inhibition of RE/AP activation. Mutation of the SH2 domain did not affect ALX expression, relative localization in the cytoplasm and nucleus, phosphorylation, or a mobility shift in response to TCR signaling alone. However, an activation-induced mobility shift triggered by CD28 was reduced in the ALX SH2 domain mutant. In addition, the isolated ALX SH2 domain was found to associate with a phosphoprotein from Jurkat T cells on TCR/CD28 stimulation. Therefore, the ALX SH2 domain plays a critical role in ALX function downstream of CD28.

Received for publication, April 15, 2004 , and in revised form, July 27, 2004.

^* This work was supported by an Arthritis Foundation Arthritis Investigator Award (to V. S. S.). 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.

To whom correspondence should be addressed: 288 John Morgan Bldg., Dept. of Pathology and Laboratory Medicine, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104. Tel.: 215-573-9260; Fax: 215-898-4227; E-mail: shapirov{at}mail.med.upenn.edu.

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