The proto-oncogene product pp60cs`c is a tyrosine-specific kinase with a still unresolved cellular function. High levels of pp60C-cs in neurons and the existence of a neuronal pp6OCSrC variant, pp60c-srCN, suggest participation in the progress or maintenance of the differentiated phenotype of neurons. We M. E. K. Mattson, U. Hammerling, E. Mohall, K. Hall, and S. Pahlman, Growth Factors, in press).Postmitotic neurons of rat brain and chicken retina show high expression of src protein and kinase activity (11,14,22,57), and the specific src kinase activity increases during in vitro differentiation of mouse embryo carcinoma cells (42) and rat striatal neurons (14). The src protein in rat brain neurons is modified in the N terminus (pp60-srcN) and has a specific tyrosine kinase activity higher than that of the nonneuronal form, pp60c-src (10, 11). However, pp6Oc-srcN isolated from established human neuroblastoma cell lines appeared not to have a specific kinase activity higher than that of pp6Oc-src prepared from fibroblasts or glioblastoma cells (48,66 (46). In this report, we show that the specific src kinase activity in SH-SY5Y cells increases threefold during neuronal differentiation induced by TPA. This increase does not involve a shift in the ratio of expressed c-src to c-srcN products.