A MUTANT FORM OF P135(TYK2), AN INTERFERON-ALPHA INDUCIBLE TYROSINE KINASE, SUPPRESSES THE TRANSFORMED PHENOTYPE OF DAUDI CELLS

The type I interferons induce an anti-viral state and suppress cell gr owth. The p135(tyk2) non-receptor tyrosine kinase appears to initiate, at least in part, the type I interferon signal transduction pathway, and thereby activates type I interferon-dependent gene expression. To determine if p135(tyk2) can suppress growth and/or tumorigenesis, deri vatives of the tyk2 gene were introduced into the tumorigenic cell lin e Daudi. Transfectants expressing a tyk2 construct missing the carboxy -terminal 22 amino acids cloned with a greatly reduced efficiency in s oft agar and displayed a partial decrease in the ability to form tumor s in athymic mice. In addition, transfectants producing a kinase defic ient version of tyk2 show an increase in both growth rate and agar clo ning efficiency, suggesting that the inactive kinase can act in a domi nant-negative manner. Surprisingly, the carboxyl-terminal deleted prot ein lacks both auto-kinase activity, and activity towards a putative s ubstrate, even though it induces a phenotype which is precisely the op posite of that produced by another kinase-deficient tyk2 mutant contai ning an altered ATP binding site. Thus, while these results add tyk2 t o a growing list of interferon-alpha regulated proteins that might be able to suppress tumor formation, the biochemical basis of this activi ty remains unknown.