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J Biol Chem, Vol. 273, Issue 32, 20487-20493, August 7, 1998

Tyrosine 474 of ZAP-70 Is Required for Association with the Shc Adaptor and for T-cell Antigen Receptor-dependent Gene Activation

Sonia Pacini, Cristina Ulivieri, M. Maddalena Di Somma^§, Antonella Isacchi, Luisa Lanfrancone^**, Pier Giuseppe Pelicci^**, John L. Telford^§, and Cosima T. Baldari

From the  Department of Evolutionary Biology, University of Siena, Via Mattioli 4, 53100 Siena,  Pharmacia & Upjohn SpA, Viale Pasteur 10, 20014 Nerviano, ^§ Chiron SpA, Via Fiorentina 1, 53100 Siena, and the ^** European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy

The protein tyrosine kinase ZAP-70 plays a central role in T-cell activation. Following receptor engagement, ZAP-70 is recruited to the phosphorylated subunits of the T-cell antigen receptor (TCR). This event results in ZAP-70 activation and in association of ZAP-70 with a number of signaling proteins. Among these is the Shc adaptor, which couples the activated TCR to Ras. Shc interaction with ZAP-70 is mediated by the Shc PTB domain. The inhibitory effect of a Shc mutant containing the isolated PTB domain suggests that Shc interaction with ZAP-70 might be required for TCR signaling. Here, we show that a point mutation (Phe⁴⁷⁴) of the putative Shc binding site on ZAP-70, spanning tyrosine 474, prevented ZAP-70 interaction with Shc and the subsequent binding of Shc to phospho-. Neither ZAP-70 catalytic activity nor the pattern of protein phosphorylation induced by TCR triggering was affected by this mutation. However expression of the Phe⁴⁷⁴ ZAP-70 mutant resulted in impaired TCR-dependent gene activation. ZAP-70 could effectively phosphorylate Shc in vitro. Only the CH domain, which contains the two Grb2 binding sites on Shc, was phosphorylated by ZAP-70. Both Grb2 binding sites were excellent substrates for ZAP-70. The data show that Tyr⁴⁷⁴ on ZAP-70 is required for TCR signaling and suggest that Shc association with ZAP-70 and the resulting phosphorylation of Shc might be an obligatory step in linking the activated TCR to the Ras pathway.

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