title: The Shc family protein adaptor, Rai, negatively regulates T cell antigen receptor signaling by inhibiting ZAP-70 recruitment and activation.
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 context of the immune synapse. Rai is moreover found as a pre-assembled complex with ZAP-70 and also constitutively interacts with the regulatory p85 subunit of PI3K, similar to neuronal cells, notwithstanding the opposite biological outcome, i.e. impairment of PI-3K/Akt activation. The data highlight the ability of Rai to establish interactions with the TCR and key signaling mediators which, either directly (e.g. by inhibiting ZAP-70 recruitment to the TCR or sequestering ZAP-70/PI3K in the cytosol) or indirectly (e.g. by promoting the recruitment of effectors responsible for signal extinction) prevent full triggering of the TCR signaling cascade.
authors.affiliation: Department of Evolutionary Biology European Institute of Oncology, Milan, Italy.
authors.forename: Micol
authors.initials: M
authors.lastname: Ferro
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Savino
authors.forename: Barbara
authors.initials: B
authors.lastname: Ortensi
authors.forename: Francesca
authors.initials: F
authors.lastname: Finetti
authors.forename: Luca
authors.initials: L
authors.lastname: Genovese
authors.forename: Giulia
authors.initials: G
authors.lastname: Masi
authors.forename: Cristina
authors.initials: C
authors.lastname: Ulivieri
authors.forename: Daniela
authors.initials: D
authors.lastname: Benati
authors.forename: Giuliana
authors.initials: G
authors.lastname: Pelicci
authors.forename: Cosima T
authors.initials: CT
authors.lastname: Baldari
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D054992:Immunological Synapses / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D055765:Shc Signaling Adaptor Proteins; C485682:Shc3 protein, mouse; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; D019869:Phosphatidylinositol 3-Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase