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J. Biol. Chem., Vol. 280, Issue 46, 38242-38246, November 18, 2005

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The Carboxyl-terminal Segment of the Adaptor Protein ALX Directs Its Nuclear Export during T Cell Activation^*

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

The adaptor protein ALX acts downstream of CD28 to regulate the interleukin-2 (IL-2) promoter during T cell activation. Whereas ALX is predominantly localized to the cytoplasm, ALX partially resides in the nucleus, and the nuclear pool is rapidly depleted in response to T cell receptor (TCR)/CD28 signaling. Here it is shown that this depletion occurs via nuclear export of ALX, which depends on a leucine-rich nuclear export signal (NES) in its carboxyl segment and on the CRM-1 transport protein. Nuclear import of ALX also depends on its carboxyl-terminal segment. Blocking nuclear export of ALX, either pharmacologically, by leptomycin B, or by site-directed mutation of the ALX NES, impairs CD28-mediated phosphorylation of ALX. Additionally, upon overexpression, the ALX NES mutant was found to be impaired in inhibiting TCR/CD28-induced transcriptional up-regulation of the RE/AP composite element from the IL-2 promoter, whereas a truncated form of ALX that is a potent inhibitor of RE/AP activation was found to reside entirely in the cytoplasm. Together, these results show that ALX exerts its effect on IL-2 up-regulation in the cytoplasm and suggest an intricate relationship between the nuclear localization/export, phosphorylation, and activity of ALX in response to TCR and CD28 signaling.

Received for publication, July 8, 2005 , and in revised form, August 8, 2005.

^* This work was supported by National Institutes of Health R01 Grant AI054974 (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.

¹ 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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