Jordan Martha S, Maltzman Jonathan S, Kliche Stefanie, Shabason Jacob, Smith Jennifer E, Obstfeld Amrom, Schraven Burkhart, Koretzky Gary A
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Eur J Immunol. 2007 Oct;37(10):2961-72. doi: 10.1002/eji.200636855.
Multi-molecular complexes nucleated by adaptor proteins play a central role in signal transduction. In T cells, one central axis consists of the assembly of several signaling proteins linked together by the adaptors linker of activated T cells (LAT), Src homology 2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76), and Grb2-related adaptor downstream of Shc (Gads). Each of these adaptors has been shown to be important for normal T cell development, and their proper sub-cellular localization is critical for optimal function in cell lines. We previously demonstrated in Jurkat T cells and a rat basophilic leukemic cell line that expression of a 50-amino acid polypeptide identical to the site on SLP-76 that binds to Gads blocks proper localization of SLP-76 and SLP-76-dependent signaling events. Here we extend these studies to investigate the ability of this polypeptide to inhibit TCR-induced integrin activity in Jurkat cells and to inhibit in vivo thymocyte development and primary T cell function. These data provide evidence for the in vivo function of a dominant-negative peptide based upon the biology of SLP-76 action and suggest the possibility of therapeutic potential of targeting the SLP-76/Gads interaction.
由衔接蛋白成核的多分子复合物在信号转导中起核心作用。在T细胞中，一个核心轴由几种信号蛋白的组装组成，这些信号蛋白通过活化T细胞衔接蛋白（LAT）、含Src同源2结构域的76 kDa白细胞特异性磷蛋白（SLP-76）和Shc下游的Grb2相关衔接蛋白（Gads）连接在一起。这些衔接蛋白中的每一种都已被证明对正常T细胞发育很重要，并且它们在亚细胞中的正确定位对于细胞系中的最佳功能至关重要。我们之前在Jurkat T细胞和大鼠嗜碱性白血病细胞系中证明，一种与SLP-76上与Gads结合的位点相同的50个氨基酸多肽的表达会阻断SLP-76的正确定位以及SLP-76依赖性信号事件。在此，我们扩展这些研究，以研究该多肽抑制Jurkat细胞中TCR诱导的整合素活性以及抑制体内胸腺细胞发育和原代T细胞功能的能力。这些数据基于SLP-76的作用生物学为显性负性肽的体内功能提供了证据，并提示了靶向SLP-76/Gads相互作用的治疗潜力。
