The zeta chain has emerged to be a key subunit of the T-cell antigen receptor with central roles not only in intracellular assembly of the multimeric receptor but also in mediating signal transduction events. This subunit is present in natural killer (NK) cells that lack the other subunits of the T-cell antigen receptor. In NK cells, the zeta chain appears to be associated with the NK Fc receptor [type 3 receptor for the Fc portion of IgG (Fc gamma RIII or CD16)] and may be necessary for efficient cell surface expression of this receptor complex. In T cells, the zeta chain is a prominent substrate that becomes phosphorylated on tyrosine residues after occupancy of the TCR; zeta chain phosphorylation was in fact the first evidence that the TCR was coupled to a protein-tyrosine kinase as well as to inositol phospholipid hydrolysis. To determine if Fc gamma RIII is coupled to a protein-tyrosine kinase in a manner analogous to the T-cell antigen receptor, we investigated ligand-dependent zeta-chain phosphorylation in NK cells. We observed that activation of NK cells with an anti-Fc gamma RIII monoclonal antibody induced tyrosine phosphorylation of the zeta chain whereas other activating stimuli, such as the combination of phorbol ester and ionomycin or a lymphokine, interleukin 2, did not result in phosphorylation of this protein. Perturbation of Fc gamma RIII by the more physiological stimulus, incubation of NK cells with antibody-coated target cells, also induced zeta-chain phosphorylation. Previous data have indicated that the NK-cell Fc gamma RIII is coupled to inositol phospholipid hydrolysis. This present finding that Fc gamma RIII is coupled to a protein-tyrosine kinase illustrates that there are significant similarities in the signaling pathways activated by Fc gamma RIII in NK cells and the T-cell antigen receptor in T cells; the zeta chain is a common element that may serve as a coupling protein for both of these receptors.