Stimulation of activated T cells with interleukin-2 (IL-2) results in the tyrosine phosphorylation of several intracellular proteins. The present studies demonstrate that IL-2 stimulation induces phosphorylation of the src homology 2 domain-containing protein, p52shc, on both tyrosine and serine residues. The level of p52shc phosphorylation was maximal within 5 min after growth factor addition and declined gradually thereafter. In addition, anti-Shc immunoprecipitates from IL-2-stimulated T cells contained a co-precipitating protein tyrosine kinase (PTK) activity that phosphorylated p52shc on tyrosine residues in immune complex kinase assays. These results demonstrate that p52shc is an early substrate for IL-2 receptor-coupled PTK activity(s) and suggest that this protein may be involved in the transduction of PTK-dependent regulatory signals in IL-2-stimulated T cells.