The T-cell receptor regulates Akt (protein kinase B) via a pathway involving Rac1 and phosphatidylinositide 3-kinase

作     者：Genot, EM Arrieumerlou, C Ku, G Burgering, BMT Weiss, A Kramer, IM 

作者机构：Univ Bordeaux 1 Growth Factors & Differentiat Lab F-33405 Talence France Univ London Imperial Coll Sci Technol & Med Dept Immunol London W12 0NN England CERVI Lab Immunol Cellulaire CNRS UMR 7627 F-75013 Paris France Univ Calif San Francisco Howard Hughes Med Inst Dept Med Microbiol & Immunol San Francisco CA 94143 USA Univ Utrecht Physiol Chem Lab NL-3584 CG Utrecht Netherlands 

出 版 物：《MOLECULAR AND CELLULAR BIOLOGY》 (分子生物学与细胞生物学)

年 卷 期：2000年第20卷第15期

页      面：5469-5478页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 07[理学] 

基　　金：Wellcome Trust Funding Source: Medline 

主　　题：色酮类/药理学 细胞骨架/代谢 细胞骨架/超微结构 酶激活 酶抑制剂/药理学 吗啉类/药理学 突变 磷酸肌醇3-激酶类/拮抗剂和抑制剂 磷酸肌醇3-激酶类/遗传学 磷酸肌醇3-激酶类/代谢 磷酰化 蛋白质丝氨酸苏氨酸激酶 原癌基因蛋白质类/代谢 原癌基因蛋白质c-akt 受体 抗原 T细胞/免疫学 受体 抗原 T细胞/代谢 T淋巴细胞/代谢 苏氨酸/代谢 肿瘤细胞 培养的 rac1GTP结合蛋白质/遗传学 rac1GTP结合蛋白质/代谢 人类 

摘      要：The serine/threonine kinase Akt (also known as protein kinase B) (Akt/PKB) is activated upon T-cell antigen receptor (TCR) engagement or upon expression of an active form of phosphatidylinositide (PI) 3-kinase in T lymphocytes. Here we report that the small GTPase Rad is implicated in this pathway, connecting the receptor with the lipid kinase. We show that in Jurkat cells, activated forms of Rad or Cdc42, but not Rho, stimulate an increase in Akt/PKB activity. TCR-induced Akt/PKB activation is inhibited either by PI 3-kinase inhibitors (LY294002 and wortmannin) or by overexpression of a dominant negative mutant of Rad but not Cdc42. Accordingly, triggering of the TCR rapidly stimulates a transient increase in GTP-Rac content in these cells. Similar to TCR stimulation, L61Rac-induced Akt/PKB kinase activity is also LY294002 and wortmannin sensitive. However, induction of Akt/PKB activity by constitutive active PI 3-kinase is unaffected when dominant negative Rad is coexpressed, placing Rad upstream of PI 3-kinase in the signaling pathway. When analyzing the signaling hierarchy in the pathway leading to cytoskeleton rearrangements, we found that Rad acts downstream of PI 3-kinase, a finding that is in accordance with numerous studies in fibroblasts. Our results reveal a previously unrecognized role of the GTPase Rad, acting upstream of PI 3-kinase in linking the TCR to Akt/PKB. This is the first report of a membrane receptor employing Rad as a downstream transducer for Akt/PKB activation.