the shc family protein adaptor, rai, negatively regulates t cell antigen receptor signaling by inhibiting zap-70 recruitment and activation自燃家族蛋白适配器,rai,负调节t细胞抗原受体信号通过抑制zap - 70招聘和激活.pdfVIP

The Shc Family Protein Adaptor, Rai, Negatively Regulates T Cell Antigen Receptor Signaling by Inhibiting ZAP-70 Recruitment and Activation 1 1 2 1 1 1 Micol Ferro , Maria Teresa Savino , Barbara Ortensi , Francesca Finetti , Luca Genovese , Giulia Masi , 1 1¤ 2 1,3 Cristina Ulivieri , Daniela Benati , Giuliana Pelicci , Cosima T. Baldari * 1 Department of Evolutionary Biology European Institute of Oncology, Milan, Italy, 2 Department of Experimental Oncology, European Institute of Oncology, Milan, Italy, 3 Istituto Toscano Tumori, University of Siena, Siena, Italy Abstract Rai/ShcC is a member of the Shc family of protein adaptors expressed with the highest abundance in the central nervous system, where it exerts a protective function by coupling neurotrophic receptors to the PI3K/Akt survival pathway. Rai is also expressed, albeit at lower levels, in other cell types, including T and B lymphocytes. We have previously reported that in these cells Rai attenuates antigen receptor signaling, thereby impairing not only cell proliferation but also, opposite to neurons, cell survival. Here we have addressed the mechanism underlying the inhibitory activity of Rai on TCR signaling. We show that Rai interferes with the TCR signaling cascade one of the earliest steps –recruitment of the initiating kinase ZAP-70 to the phosphorylated subunit of the TCR/CD3 complex, which results in a generalized dampening of the downstream signaling events. The inhibitory activity of Rai is associated to its inducible recruitment to phosphorylated CD3, which occurs in the physiological signaling c