Gupta Sanjay, Fanzo Jessica C, Hu Chuanmin, Cox Dianne, Jang So Young, Lee Andrea E, Greenberg Steven, Pernis Alessandra B
Departments of Medicine and Medicine and Pharmacology, Columbia University, New York, New York 10032, USA.
J Biol Chem. 2003 Oct 31;278(44):43541-9. doi: 10.1074/jbc.M308960200. Epub 2003 Aug 15.
Reorganization of the actin cytoskeleton is crucial to the formation and function of the immunological synapse. Rho GTPases are critical mediators of cytoskeletal reorganization, and their activity at the synapse is likely to be stringently regulated. Guanine nucleotide exchange factors (GEFs) belonging to the Dbl family of proteins represent one major class of proteins that regulate the activity of Rho GTPases. Here we demonstrate that IBP, a homologue of SWAP-70, is a novel GEF for Rac1 and Cdc42 in T lymphocytes, which is recruited to the immunological synapse upon engagement of the antigen receptor. Mutational analysis supports a model whereby IBP is inactive in unstimulated cells. Upon engagement of the T cell receptor, its GEF activity is enhanced by tyrosine phosphorylation, as well as by binding newly generated phosphatidylinositol 3,4,5-trisphosphate. Although it is known that T cell receptor engagement leads to the recruitment of Vav to the immunological synapse, these findings indicate that other GEFs, such as IBP, also relocalize to this intercellular region. The recruitment and activation of distinct classes of GEFs may allow for precise control of Rho GTPase function at the crucial interface between T cells and antigen presenting cells.
肌动蛋白细胞骨架的重组对于免疫突触的形成和功能至关重要。Rho GTP酶是细胞骨架重组的关键介质，它们在突触处的活性可能受到严格调控。属于Dbl家族蛋白的鸟嘌呤核苷酸交换因子（GEF）是调节Rho GTP酶活性的一类主要蛋白质。在这里，我们证明IBP是SWAP-70的同源物，是T淋巴细胞中Rac1和Cdc42的新型GEF，在抗原受体结合后被招募到免疫突触。突变分析支持一种模型，即IBP在未受刺激的细胞中无活性。在T细胞受体结合后，其GEF活性通过酪氨酸磷酸化以及结合新生成的磷脂酰肌醇3,4,5-三磷酸而增强。虽然已知T细胞受体结合会导致Vav招募到免疫突触，但这些发现表明其他GEF，如IBP，也会重新定位到这个细胞间区域。不同类型GEF的招募和激活可能允许在T细胞和抗原呈递细胞之间的关键界面精确控制Rho GTP酶的功能。
