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Volume 271, Number 34, Issue of August 23, 1996 pp. 20494-20500
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Interferon--dependent Activation of Tyk2 Requires Phosphorylation of Positive Regulatory Tyrosines by Another Kinase

(Received for publication, March 5, 1996, and in revised form, May 7, 1996)

From the Institut Pasteur, INSERM U 276, Paris 75724 Cedex 15, France and ^'' Institut de Génétique Moléculaire, CNRS UMR 9942 Montpellier, France

Tyk2 and JAK1, members of the Janus kinase (JAK) family of protein tyrosine kinases, are required for interferon-/ binding and signaling. Both enzymes are associated with the interferon-/ receptor, and upon ligand binding, they undergo tyrosine phosphorylation and catalytic activation in an interdependent manner. To identify residues involved in Tyk2 regulation and to understand the basis of the interdependence of Tyk2 and JAK1, six mutated versions of Tyk2 bearing single or multiple point mutations in the tyrosine kinase domain were studied in a cell line lacking endogenous Tyk2. The Y1054F/Y1055F substitutions in the putative activation loop prevented ligand-dependent activation of Tyk2, without abolishing its catalytic potential. The K930R mutation in the ATP binding site generated a kinase-negative protein, which however, still became phosphorylated upon interferon- treatment. The Y1054F/Y1055F substitutions in this kinase-negative Tyk2 abolished the induced phosphorylation. These results indicate that Tyk2 is activated by phosphorylation on Tyr-1054 and/or Tyr-1055 and that this phosphorylation requires another kinase, most likely JAK1. While the Tyk2 forms mutated on Tyr-1054 and Tyr-1055 or on Lys-930 allowed some inducible gene expression, the combination of the three point mutations totally abolished signaling.

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