Following induction of cell differentiation in vitro, an increase in Syk activity was observed only in HL60 cells differentiation into granulocytes induced by all trans retinoic acid (RA) but not into macrophages induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) or monocytes induced by sodium butyrate. This elevation of Syk activity was the specific increase in kinase activity because the Syk amount was not altered before and after differentiation. Anti-phosphotyrosine blot revealed that tyrosine phosphorylation of Syk was significantly increased as the function of induction time by RA, but not by TPA and sodium butyrate, suggesting that tyrosine phosphorylation might account for Syk activation. More importantly, Syk tyrosine phosphorylation and Syk activity were not altered in U937 and K562 cells which undergo monocyte differentiation and no differentiation, respectively, in response to RA induction. Taken together, Syk might exert a unique role in directing HL60 cells toward granulocyte differentiation. (C) 1997 Academic Press.