Catalytic ally active TYK2 is essential for interferon-beta-mediated phosphorylation of STAT3 and interferon-alpha receptor-1 (IFNAR-1) but not for activation of phosphoinositol 3-kinase

TYK2, a Janus kinase, plays both structural and catalytic roles in type I i nterferon (IFN) signaling. We recently reported (Rani, M. R. S., Gauzzi, C. , Pellegrini, S., Fish, E., Wei, T., and Ransohoff, R. M. (1999) J. Biol. C hem. 274, 1891-1897) that catalytically active TYK2 was necessary for IFN-b eta to induce the beta-R1 gene. We now report IFN-beta-mediated activation of STATs and other components in UI (TYK2-null) cell lines that were comple mented with kinase-negative (U1.KR930) or wildtype TYK2 (U1.wt), We found t hat IFN-beta induced phosphorylation on tyrosine of STAT3 in U1.wt cells bu t not in U1.KR930 cells, whereas STAT1 and STATE were activated in both cel l lines. Additionally, IFN-beta-mediated phosphorylation of interferon-alph a receptor-1 (IFNAR-1) was defective in IFN-beta treated U1.KR930 cells, bu t evident in U1.wt cells, In U1A-derived cells, the p85/p110 phosphoinosito l 3-kinase isoform was associated with IFNAR-1 but not STAT3, and the assoc iation was ligand-independent. Further, IFN-beta treatment stimulated IFNAR -1-associated phosphoinositol kinase activity equally in either U1.wt or U1 .KR930 cells. Our results indicate that catalytically active TYK2 is requir ed for IFN-beta-mediated tyrosine phosphorylation of STAT3 and IFNAR-1 in i ntact cells.