Abstract: Two HTLV-I infected rabbit T cell lines differ in that one of them, RH/K34, causes leukemia-like disease, whereas the second, RH/K30, mediates asymptomatic infection. The two cell lines have minor differences in sequence of the integrated proviruses and in surface molecule expression, but the proto-oncogene product Vav is tyrosine phosphorylated (P-Tyr) in RH/K34 but not in RH/K30. Further examination of the cell lines revealed that the oncogene product c-Cbl is constitutively phosphorylated in RH/K34, but not in RH/K30. Anti-Cbl precipitates from RH/K34 contained Cbl along with an associated protein of 55-60 kDa of unknown identity which was revealed by anti P-Tyr. Activation of RH/K34 cells with pervanadate phosphates inhibitor enhances phosphorylation of Cbl and increases the number of associated molecules; similar treatment of RH/K30 induces phosphorylation of Cbl, but no molecular associations are seen. In vitro association of Cbl with other signaling molecules was stronger through SH-3 than SH-2 domains. Viral DNA clones corresponding to either RH/K30 or RH/K34 downregulated Cbl phosphorylation in a rabbit T-cell line upon transfection. These data indicate differential influence of HTLV-I on phosphorylation of oncogene products and raise questions concerning their role in pathogenesis.