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The epidermal growth factor receptor (EGFR) is activated by ionizing radiation (IR) in many human carcinomas, mediating a cytoprotective response and subsequent radioresistance. The underlying molecular mechanisms remain to be understood, and we propose here a specific role for the Tyr-992 residue of EGFR and examine its regulation by the phosphatase, SHP2. The -fold increase in phosphorylation of Tyr-992 in response to IR is twice that seen with ligand (EGF) binding. Mutation of Tyr-992 blocked completely IR-induced EGFR phosphorylation and reduced activation of the downstream signaling molecule, phospholipase C␥. IR has previously been demonstrated to inhibit activity of protein-tyrosine phosphatases. Following protein-tyrosine phosphatase inhibition by sodium vanadate both EGFR expressing Chinese hamster ovary (CHO) and A431 exhibited up to an 8-fold increase in the basal level of Tyr-992 phosphorylation, significantly higher than that seen with Tyr-1173, Tyr-1068, and total EGFR Tyr. CHO cells expressing a SHP2 mutant also demonstrated up to an 8-fold increase in the basal level of Tyr-992 phosphorylation. In this study we show the unique association of SHP2 with EGFR in response to IR, with up to a 2.5-fold increase in the direct association of endogenous SHP2 with EGFR-wt in response to 2 gray of IR in both CHO and A431 cells. Mutation of Tyr-992 abolished this response. In conclusion we have identified several differentially activated Tyr residues, one of which is not only more sensitive to activation by IR, translating into differential activation of downstream signaling, but uniquely modulated by the phosphatase SHP2.