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J. Biol. Chem., Vol. 280, Issue 25, 23576-23583, June 24, 2005

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Deficiency of ADAP/Fyb/SLAP-130 Destabilizes SKAP55 in Jurkat T Cells^*

Yanping Huang, Darrell D. Norton, Patricia Precht, Jennifer L. Martindale, Janis K. Burkhardt¶, and Ronald L. Wange||

From the Laboratory of Cellular and Molecular Biology, NIA, National Institutes of Health, Intramural Research Program/Department of Health and Human Services, Baltimore, Maryland 21224, and the ^¶Department of Pathology, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania 19104

ADAP (adhesion and degranulation-promoting adaptor protein) and SKAP55 (Src kinase-associated phosphoprotein of 55 kDa) are T cell adaptors that mediate inside-out signaling from the T cell antigen receptor to integrins, giving rise to increased integrin affinity/avidity and formation of the immunological synapse between the T cell and the antigen-presenting cell. These two proteins are tightly and constitutively associated with one another, and their ability to interact is required for inside-out signaling. Here we show in an ADAP-deficient Jurkat T cell line that the co-dependence of ADAP and SKAP55 extends beyond their functional and physical interactions and show that SKAP55 protein is unstable in the absence of ADAP. Restoration of ADAP to the ADAP-deficient Jurkat T cell line restores SKAP55 expression by causing a 5-fold decrease in the rate of SKAP55 proteolysis. Inactivation of the Src homology 3 domain of SKAP55, which mediates the association between SKAP55 with ADAP, blocks the protective effect of ADAP. The half-life of SKAP55, in the absence of ADAP, is 15–20 min, increasing to 90 min in the presence of ADAP. This is a remarkably rapid rate of turnover for a signaling protein and suggests the possibility that stimuli that signal for the stabilization of SKAP55 may play an important role in T cell adhesion and conjugate formation.

Received for publication, November 23, 2004 , and in revised form, April 19, 2005.

^* 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.

^|| Present address: Center for Drug Evaluation and Research, Food & Drug Administration, 5600 Fishers Ln., HFD-510, Rockville, MD 20857.

To whom correspondence should be addressed: 815D Abramson Research Center, Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104-4399. Tel.: 267-426-5523/5524; Fax: 267-426-5165; E-mail: HUANGY{at}email.chop.edu.

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