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Genetic Analysis of SH2D4A, a Novel Adapter Protein Related to T Cell-Specific Adapter and Adapter Protein in Lymphocytes of Unknown Function, Reveals a Redundant Function in T Cells¹

Philip E. Lapinski^*, Jennifer A. Oliver^*, Lynn A. Kamen^*, Elizabeth D. Hughes, Thomas L. Saunders^, and Philip D. King^2,*

^* Department of Microbiology and Immunology, Transgenic Animal Model Core, and Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor, MI 48109

T cell-specific adapter (TSAd) protein and adapter protein in lymphocytes of unknown function (ALX) are two related Src homology 2 (SH2) domain-containing signaling adapter molecules that have both been shown to regulate TCR signal transduction in T cells. TSAd is required for normal TCR-induced synthesis of IL-2 and other cytokines in T cells and acts at least in part by promoting activation of the LCK protein tyrosine kinase at the outset of the TCR signaling cascade. By contrast, ALX functions as a negative-regulator of TCR-induced IL-2 synthesis through as yet undetermined mechanisms. In this study, we report a novel T cell-expressed adapter protein named SH2D4A that contains an SH2 domain that is highly homologous to the TSAd protein and ALX SH2 domains and that shares other structural features with these adapters. To examine the function of SH2D4A in T cells we produced SH2D4A-deficient mice by homologous recombination in embryonic stem cells. T cell development, homeostasis, proliferation, and function were all found to be normal in these mice. Furthermore, knockdown of SH2D4A expression in human T cells did not impact upon their function. We conclude that in contrast to TSAd and ALX proteins, SH2D4A is dispensable for TCR signal transduction in T cells.

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 This work was supported by Grants 0615514Z and 08501702 from the American Heart Association and by Grant AI050699 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Philip D. King, Department of Microbiology and Immunology, University of Michigan Medical School, 6606 Medical Science II, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0620. E-mail address: kingp{at}umich.edu

³ Abbreviations used in this paper: TSAd, T cell-specific adapter; SH2, Src homology 2; siRNA, small interfering RNA; DC, dendritic cell; ES, embryonic stem cell; HA, hemagglutinin; DN, double negative; ALX, adapter protein in lymphocytes of unknown function.