A mutant form of p135tyk2, 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 growth. The p135tyk2 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 p135tyk2 can suppress growth and/or tumorigenesis, derivatives of the tyk2 gene were introduced into the tumorigenic cell line Daudi. Transfectants expressing a tyk2 construct missing the carboxy-terminal 22 amino acids cloned with a greatly reduced efficiency in soft agar and displayed a partial decrease in the ability to form tumors in athymic mice. In addition, transfectants producing a kinase deficient version of tyk2 show an increase in both growth rate and agar cloning efficiency, suggesting that the inactive kinase can act in a dominant-negative manner. Surprisingly, the carboxyl-terminal deleted protein lacks both auto-kinase activity, and activity towards a putative substrate, even though it induces a phenotype which is precisely the opposite of that produced by another kinase-deficient tyk2 mutant containing an altered ATP binding site. Thus, while these results add tyk2 to a growing list of interferon-alpha regulated proteins that might be able to suppress tumor formation, the biochemical basis of this activity remains unknown.
Davis
E
E
Department of Pathology and Columbia-Presbyterian Cancer Center, Columbia University, College of Physicians and Surgeons, New York, 10032, USA.
Krishnan
K
K
Yan
H
H
Newcomb
E W
EW
Krolewski
J J
JJ
D000818:Animals; D015152:Blotting, Northern; D002051:Burkitt Lymphoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002455:Cell Division; D004790:Enzyme Induction; D016147:Genes, Tumor Suppressor; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D010641:Phenotype; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases; D011506:Proteins / Q000235:genetics*; D015398:Signal Transduction; D053634:TYK2 Kinase; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000201:enzymology; D014410:Tumor Stem Cell Assay
D016898:Interferon-alpha; D011506:Proteins; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse