Activation of the Phosphatidylinositol 3-Kinase Serine Kinase by IFN-α

Shahab Uddin, Eleanor N. Fish, Dorie A. Sher, Concetta Gardziola, Morris F. White, Leonidas C. Platanias*

*Corresponding author for this work

Research output: Contribution to journalArticle

126 Scopus citations

Abstract

During engagement of the type I IFN receptor, IRS-1 is phosphorylated on tyrosine and associates with the p85 regulatory subunit of the phosphatidylinositol (PI) 3′-kinase, which is a dual-specificity enzyme possessing both lipid and serine kinase activities. We sought to determine whether treatment of cells with IFN-α activates the PI 3′-kinase serine kinase. 32P-labeling experiments and phosphoaminoacid analysis of immunoprecipitated IRS-1 protein demonstrated that, in addition to tyrosine phosphorylation, IFN-α induces its phosphorylation on serine residues. In vitro kinase assays on αIRS-1 immunoprecipitates also demonstrated IFN-α-dependent serine phosphorylation of IRS-1, suggesting that the protein associates with an IFN-a-regulated serine kinase. Furthermore, IFN-α-dependent phosphorylation of IRS-1 was detected in in vitro kinase assays on αp85 immunoprecipitates, and was inhibited by pretreatment of cells with the specific PI 3′-kinase inhibitor wortmannin, consistent with a regulatory role of the PI 3′-kinase serine kinase on the phosphorylation of the protein. Treatment of cells with wortmannin also inhibited the phosphorylation of the p85 subunit of PI 3′-kinase and the type I IFN-regulated activation of the Map kinase, but had no inhibitory effect on the IFN-α-induced activation of Tyk-2 and Jak-1 kinases nor on the activation of Stat-1, Stat-2, and Stat-3. Taken all together, these data establish that the PI 3′-kinase serine kinase is activated by IFN-α and may play an important role in the transmission of type I IFN receptor-generated signals.

Original languageEnglish (US)
Pages (from-to)2390-2397
Number of pages8
JournalJournal of Immunology
Volume158
Issue number5
StatePublished - Mar 1 1997

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Uddin, S., Fish, E. N., Sher, D. A., Gardziola, C., White, M. F., & Platanias, L. C. (1997). Activation of the Phosphatidylinositol 3-Kinase Serine Kinase by IFN-α. Journal of Immunology, 158(5), 2390-2397.