The hematopoietic lineage derivation, recognition structures and associated signal transduction pathways of CD3- natural killer (NK) cells have not been identified. Protein tyrosine kinases (PTK) structurally related to the product of the c-src protooncogene are differentially expressed in distinct hematopoietic differentiation lineages and may participate in specific signal transduction pathways. The present study was aimed at characterizing the expression of src-related PTK genes in normal human NK cells and in cells from patients with CD3- granular lymphocyte proliferative disease. CD3- normal NK cells had high levels of transcripts of the lck gene, which is highly expressed in T cells. CD8+ and CD8- NK cells expressed similarly high levels of lck mRNA. In contrast, NK cells expressed very low levels (25-80 times less than monocytes) of mRNA encoding the myelomonocytic PTK hck. NK cells also expressed fyn transcripts (p59fyn reportedly associates with the T cell receptor in T cells) and fgr transcripts, the latter observation confirming a previous report. The pattern of expression of the lineage-restricted PTKs lck and hck in NK cells is consistent with the hypothesis of an ontogenic relationship of this population with the lymphocytic rather than myelocytic differentiation pathway. PTK expressed in NK cells may participate in signal transduction pathways in this cell population.