The envelope glycoprotein of Friend spleen focus-forming virus covalently interacts with and constitutively activates a truncated form of the receptor tyrosine kinase Stk

The Friend spleen focus-forming virus (SFFV) encodes a unique envelope glyc oprotein, gp55, which allows erythroid cells to proliferate and differentia te in the absence of erythropoietin (Epo). SFFV gp55 has been shown to inte ract with the Epo receptor complex, causing constitutive activation of vari ous signal-transducing molecules. When injected into adult mice, SFFV induc es a rapid erythroleukemia, with susceptibility being determined by the hos t gene Fv-2, which was recently shown to be identical to the gene encoding the receptor tyrosine kinase Stk/Ron. Susceptible, but not resistant, mice encode not only full-length Stk but also a truncated form of the kinase, sf -Stk, which may mediate the biological effects of SFFV infection. To determ ine whether expression of SFFV gp55 leads to the activation of sf-Stk, we e xpressed sf-Stk, with or without SFFV gp55, in hematopoietic cells expressi ng the Epo receptor. Our data indicate that sf-Stk interacts with SFFV gp55 as well as gp55(P), the biologically active form of the viral glycoprotein , forming disulfide-linked complexes. This covalent interaction, as well as noncovalent interactions with SFFV gp55, results in constitutive tyrosine phosphorylation of sf-Stk and its association with multiple tyrosine-phosph orylated signal-transducing molecules. In contrast, neither Epo stimulation in the absence of SFFV gp55 expression nor expression of a mutant of SFFV that cannot interact with sf-Stk was able to induce tyrosine phosphorylatio n of sf-Stk or its association with any signal-transducing molecules. Coval ent interaction of sf-Stk with SFFV gp55 and constitutive tyrosine phosphor ylation of sf-Stk can also be detected in an erythroleukemia cell line deri ved from an SFFV-infected mouse. Our results suggest that SFFV gp55 may med iate its biological effects in vivo by interacting with and activating a tr uncated form of the receptor tyrosine kinase Stk.