P135(TYK2), AN INTERFERON-ALPHA-ACTIVATED TYROSINE KINASE, IS PHYSICALLY ASSOCIATED WITH AN INTERFERON-ALPHA RECEPTOR

Recent genetic studies have linked the tyk2 gene, which encodes a nove l type of non-receptor tyrosine kinase, to the interferon-alpha intrac ellular signaling pathway. In this report, biochemical evidence is pre sented which supports this proposed function for the tyk2 tyrosine kin ase and further defines its role in the interferon-alpha signaling cas cade. Specifically, the tyk2 gene is shown to encode a 135-kDa protein which is rapidly phosphorylated on tyrosine in response to interferon -alpha treatment. Indirect evidence suggests that the tyrosine phospho rylation of p135tyk2 is the result of autokinase activity, implying th at the Tyk2 tyrosine kinase is activated by interferon-alpha treatment . Two complementary methods demonstrate a physical association between p135tyk2 and the alpha-subunit of the interferon-alpha receptor. Firs t, immunoblots show that monoclonal antibodies against the alpha-subun it of the interferon-alpha receptor can coimmunoprecipitate p135tyk2. Second, interferon-alpha receptor proteins which have been labeled by affinity cross-linking with I-125-interferon-alpha2 can be coimmuno-pr ecipitated using anti-tyk2 antisera. Taken together, these data sugges t that an interferon-a receptor-p135tyk2 complex functions, in a manne r analogous to the CD4-Ick tyrosine kinase complex, to initiate the in terferon-alpha signaling cascade.