Tyrosine-specific protein kinase activity of the epidermal growth factor (EGF) receptor, pp60"mc and ppllOgw"w was inhibited in vitro by an isoflavone genistein.The inhibition was competitive with respect to ATP and noncompetitive to a phosphate acceptor, histone H2B.By contrast, genistein scarcely inhibited the enzyme activities of serine-and threonine-specific protein kinases such as CAMP-dependent protein kinase, phosphorylase kinase, and the Ca2+/phospholipiddependent enzyme protein kinase C. When the effect of genistein on the phosphorylation of the EGF receptor was examined in cultured A43 1 cells, EGF-stimulated serine, threonine, and tyrosine phosphorylation was decreased.Phosphoamino acid analysis of total cell proteins revealed that genistein inhibited the EGFstimulated increase in phosphotyrosine level in A431 cells.Tyrosine-specific protein kinase activity is known to be associated with oncogene products of the retroviral src gene family (1-3).This kinase activity is strongly correlated with the ability of retroviruses to transform cells, since mutants with reduced kinase activity have lower transforming efficiency, and mutants which lack tyrosine kinase activity are transformation-defective (4).Similar kinase activity is also associated with the cellular receptors for several growth factors such as EGF' (5), platelet-derived growth factor (6, 7), insulin (8,9), and insulin-like growth factor I (10, 11).Therefore, it is possible that tyrosine pohosphorylation plays an important role for cell proliferation and cell transformation.According to this hypothesis, a specific inhibitor for tyrosine kinases could be an antitumor agent as well as a tool for